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What was the dosage of drug 'FLUCONAZOLE'? | Meropenem-induced pancytopenia in a preterm neonate: a case report.
BACKGROUND
A post-marketing surveillance study has reported an association between meropenem use and the incidence of hematologic abnormalities, including leukopenia, thrombocytopenia, hemolysis, and neutropenia, but the precise incidence in neonates is unknown. Here, we report meropenem-induced pancytopenia in a preterm neonate.
METHODS
A preterm newborn Pakistani received intravenous meropenem 40 mg/kg every 8 hours to treat Klebsiella pneumoniae in blood cultures and suspected meningitis. The baby developed severe thrombocytopenia, with a platelet count of 22 × 103 cells/mm3, low hemoglobin level of 9.7 g/dl, and low absolute neutrophil count (ANC) of 816 cells/mm3 on days 3, 14, and 17 of meropenem therapy, respectively. Based on the blood culture and institutional guidelines, meropenem treatment was continued with monitoring and supportive care for a total of 19 days. After discontinuation of meropenem, the baby was monitored continuously for hematological changes, and low counts persisted for 3 days. ANC improved to > 1500 cells/mm3 on the fourth day, and the platelet count reached > 150 × 103 cells/mm3 for the first time on the seventh day of meropenem discontinuation. All subsequent complete blood count (CBC) reports showed improving trends. The baby was discharged on the 48th day of life (DOL), with follow-up monitoring of CBC. The baby was kept on iron supplements, and hemoglobin level of 11.2 g/dl was observed on the 59th DOL.
CONCLUSIONS
Neonatal pancytopenia may lead to serious health complications; therefore, clinicians and pharmacists need to vigilantly monitor CBC in this vulnerable population, even when administering meropenem in septic doses for the recommended duration.
Background
Pancytopenia is defined as reduced white blood cell (WBC) count, hemoglobin, and platelet count. Pancytopenia occurs when hemoglobin is < 13 g/dl in males and < 12 g/dl in females, absolute neutrophil count (ANC) is < 1500 cells/mm3, and platelet count is < 150 × 103 cells/mm3 [1]. Pancytopenia is considered severe if a patient experiences two or more of the following: hemoglobin < 7 g/dl, ANC < 500 cells/mm3, and platelet count < 50 × 103 cells/mm3. The mechanism underlying pancytopenia mainly involves bone marrow infiltration, bone marrow aplasia, and blood cell destruction that results in peripheral blood leakage [1]. Suppression of bone marrow varies widely in the pediatric population but may occur due to toxins, infection, or malignant cell infiltrates that can lead to hypocellular bone marrow function. Drug-induced pancytopenia is also a rare but secondary cause of bone marrow suppression due to direct bone marrow toxicity, immune-mediated (complement or antibody-mediated) cell destruction, and hapten formation, and directly affects myeloid precursors [2, 3]. An in vitro study of several beta-lactam antibiotics established the presence of well-differentiated myeloid cells and copious granulocyte precursors along with dose-dependent suppression of granulopoiesis [4]. Antibody-mediated hemolytic anemia and thrombocytopenia have also been established in meropenem-treated patients [5, 6]. Several medications can cause pancytopenia including chemotherapeutics, antiepileptics, antidepressants, and antibiotics [3, 5, 7]. A case–control epidemiological surveillance study was conducted over a follow-up period of 78.7 million person-years to assess the incidence of drug-induced agranulocytosis. Around 396 confirmed cases of acute neutropenia were observed, with an overall incidence of 3.5:1 million per year [8]. It was found that agranulocytosis clearly increased the risk of mortality, with a fatality rate of 9.1%. The most common drugs causing agranulocytosis were dipyrone (16%), beta-lactam antibiotics (12.0 %), ticlopidine (11.1%), antithyroid drugs (7.2%), and sulfonamide antibiotics (5.4%) [8].
Meropenem is one of the beta-lactam antibiotics that can cause serious and life-threatening neutropenia. It is a bactericidal broad-spectrum antibiotic with gram-positive, gram-negative, and anaerobic coverage, and is mainly used in the treatment of severe gram-negative infections in neonates including severe sepsis, meningitis, and complicated intra-abdominal infections such as necrotizing enterocolitis (NEC), one of the most common gastrointestinal emergencies and a major cause of morbidity and mortality in preterm neonates. For improved clinical outcomes, early recognition and aggressive management with broad-spectrum or combination antimicrobial agents is most often undertaken to treat NEC [9]. Because of its broad-spectrum activity, meropenem is an agent of great utility [10]. Based on the increasing trends of morbidity and mortality due to multidrug-resistant gram-negative bacterial infections in our neonatal intensive care unit (NICU), and following institutional guidelines, other antibiotics such as vancomycin and colistin are also used [11–13] after infectious disease (ID) consultation. The most common adverse effects of meropenem are constipation or diarrhea, nausea, vomiting, rashes, and diaper-area moniliasis in pediatric patients [14]. Some cases of meropenem-induced neutropenia have been reported [15]. However, no known case of meropenem-induced pancytopenia in neonates has yet been published. Here we report an event of meropenem-induced pancytopenia in a neonate admitted to the NICU of a tertiary-care hospital.
Case presentation
A newborn Pakistani baby was transferred to the intensive care unit due to prematurity, low birth weight, and intrauterine growth retardation. Her birth weight was 0.71 kg and APGAR scores were 3 at 1 minute and 4 at 5 minutes. Delivered by emergency C-section at 29 weeks due to raised blood pressure and fetal distress, she was initially kept on continuous positive airway pressure (CPAP) and given nothing through the mouth, and total parenteral nutrition (TPN) was started. Caffeine was loaded at 20 mg/kg and continued as the standard of care for apnea of prematurity. A prophylactic dose of 1 mg of vitamin K was given. During the first 24 hours, complete blood count (CBC) results were WBC of 18.3 × 103 cells/mm3, ANC of 1244 cells/mm3, platelet count of 166 × 103 cells/mm3, and hemoglobin of 17.8 g/dl. On the second day of life (DOL), ampicillin and gentamicin were started as empirical therapy, and the CBC report showed WBC 4 × 103 cells/mm3, ANC of 760 cells/mm3, platelet count of 152 × 103 cells/mm3, and hemoglobin of 15.9 g/dl. In addition, fluconazole was started as antifungal prophylaxis. The patient was given phototherapy. Chest X-ray and ultrasound of the head were performed, with normal findings. CPAP was tapered to high flow on merit, and blood culture was sent.
On the fourth DOL, the baby developed issues of severe respiratory distress and abdominal distension along with metabolic acidosis. She was intubated and kept on synchronized intermittent mandatory ventilation (SIMV) mode. The CBC results showed ANC of 912 cells/mm3, platelet count of 99 × 103 cells/mm3, and hemoglobin of 12.7 g/dl. Inotropic support was started, and antibiotics were escalated to meropenem 20 mg/kg every 12 hours, vancomycin 10 mg/kg once daily, and colistin at a loading dose of 5 mg/kg with a maintenance dose of 1.5 mg/kg every 12 hours. Blood culture showed no growth. After ID consult, vancomycin was discontinued on the third day and a decision was made to continue meropenem and colistin [11–13] to manage NEC and sepsis.
On the fifth DOL, echocardiogram was performed and showed patent ductus arteriosus (PDA) of 3 mm with severe persistent pulmonary hypertension of the newborn (PPHN). Acetaminophen was started for the next 5 days. On the sixth day of meropenem therapy, the platelet count dropped to 42 × 103 cells/mm3, treated in line with sepsis-associated thrombocytopenia [16], and managed by transfusion of 10 ml/kg platelet units [17]. Meropenem and colistin were discontinued on the eighth day of therapy, and trophic feeding was started. An echocardiogram was repeated on day 11, which showed a closed PDA and moderate PPHN. On the 18th DOL, the child was successfully extubated and kept on high-flow oxygen. There was slow progress in feeding.
On the 22nd DOL, the baby had tachycardia and an episode of 99.7 °F fever. Thus, septic workup was done and showed WBC count of 17.4 × 103 cells/mm3, ANC of 12,632.4 cells/mm3, and platelets of 203 × 103 cells/mm3. C-reactive protein (CRP) was 77 mg/l and renal function was normal (blood urea nitrogen [BUN] of 11 mg/dl and creatinine of 0.2 mg/dl). Meropenem was started in meningitic doses of 40 mg/kg every 8 hours [10] along with vancomycin 15 mg/kg every 12 hours.
In the microbiological investigation, urine and cerebrospinal fluid (CSF) cultures were found to be negative, but the blood culture was positive for Staphylococcus species (not aureus). Blood culture repeated after 48 hours was positive for carbapenem-sensitive Klebsiella pneumoniae. The baby was moved to the isolation room. On the 24th DOL, the baby developed severe thrombocytopenia, with a platelet count of 22 × 103 cells/mm3, managed with the transfusion of 10 ml/kg platelet units [17].
On the 25th DOL, an episode of generalized tonic-clonic fit occurred for which single-dose diazepam and a loading dose of phenobarbitone were given initially and then continued with maintenance doses of phenobarbitone. Due to significant metabolic acidosis and desaturation, the baby was re-intubated. After ID consult, meropenem was continued in meningitic doses and vancomycin was discontinued. SIMV and a central line were placed. TPN was started with nothing per oral status.
Blood gases were monitored, and the baby was extubated after 4 days and switched to CPAP. Phenobarbitone was discontinued after 6 days of therapy, and the baby was seizure-free through the remainder of the hospital stay. All repeat blood cultures were negative for any growth including CSF culture. The ID team was on board and decided to continue meropenem for a total of 14 days post-negative culture in septic doses of 20 mg/kg, and vancomycin was discontinued after 6 days. All repeated blood cultures obtained on the 27th and 30th DOL confirmed no pathogenic growth.
On the 33rd DOL, the CBC report showed WBC of 8.7 × 103 cells/mm3, ANC of 4576 cells/mm3, platelets of 78 × 103 cells/mm3, and hemoglobin of 10.8 g/dl. On the 36th DOL, the CBC report showed WBC of 5.1 × 103 cells/mm3, ANC of 2917 cells/mm3, platelets of 29 × 103 cells/mm3, and hemoglobin of 9.2 g/dl. The baby was managed for thrombocytopenia with platelet transfusion.
On the 37th DOL, hemoglobin dropped to 8.3 g/dl in the evening, and platelet count improved to 63 × 103 cells/mm3, WBC was 4.8 × 103 cells/mm3, and ANC was 1285 cells/mm3. On the 39th DOL, a marked reduction was observed in ANC to 816 cells/mm3, platelets of 38 × 103 cells/mm3, and hemoglobin of 8.3 g/dl, and the baby received blood transfusion to manage it. For constant issues, a hematological consult was taken and a decision was made to manage the baby symptomatically with 10 ml/kg platelet units at a platelet count < 50 [17] and 15 ml/kg packed cell transfusion at hemoglobin < 10 g/dl [18].
On the 40th DOL, meropenem was discontinued 14 days after negative culture (total of 19 days of meropenem therapy). On the same day the platelet count was 34 × 103 cells/mm3, ANC was 818 cells/mm3, and hemoglobin was 10.2 g/dl, and the baby was transfused to manage these issues. After discontinuation of meropenem, the baby was continuously monitored for hematological changes, and low counts persisted for 3 days. Improved ANC of > 1500 cells/mm3 was reported on the fourth day, and platelet count of > 150 × 103 cells/mm3 was reported for the first time on the sixth day of meropenem discontinuation, but hemoglobin was still low (Fig 1). CPAP was tapered gradually to nasal prongs. The peripherally inserted central catheter was removed, and orogastric (OG) tube feeding was commenced. The baby was discharged on the 48th DOL on iron supplements with follow-up monitoring of CBC. Hemoglobin level of 11.2 g/dl was found on the 59th DOL.Fig. 1. Hematological changes and timing of medication during hospitalization
Discussion
Drug-induced pancytopenia is a rare hematological problem in neonatal clinical practices, evaluated based on a complete underlying pathological history, physical examination, and vigilant interpretation of biochemical, radiological, histopathological, and hematological findings [19]. Concerns have been raised about hematological adverse effects of several beta-lactamase inhibitors [8]. This neonatal case documents meropenem-induced pancytopenia and emphasizes cautious laboratory monitoring for patients receiving meropenem therapy.
Sepsis is another known etiology of pancytopenia. Although the neonate in the present case had a blood culture positive for K. pneumoniae, the results of all repeated blood cultures were negative, showing the resolution of sepsis. Van Tuyl et al. [20] also reported a case of a neonate receiving meropenem in meningitic doses of 40 mg/kg/day to treat meropenem-susceptible Enterobacter cloacae in blood culture. The baby developed meropenem-induced neutropenia on the 13th day of therapy, with ANC of 288 cells/mm3. The decision was made to discontinue meropenem on the 19th day of therapy instead of the initially planned 21 days. In the present case, the baby continued to receive meropenem treatment and was managed for hematological problems based on institutional guidelines and culture sensitivity. Initially, hematological changes were not considered as directly meropenem-induced.
Recently published reports also support the notion of carbapenem-induced hematological disorders. A case report by Estella and colleagues [21] described meropenem-induced pancytopenia in a 3-year-old patient at 100 mg/kg given every 8 hours to manage the regrowth of meropenem-sensitive Morganella morganii in CSF cultures. Huang et al. [6] reported a case of meropenem-induced immune thrombocytopenia in a 59-year-old patient, by detecting meropenem-dependent platelet antibodies and platelet count recovery after discontinuation of meropenem. Oka et al. [5] reported the development of severe anemia with clinical signs in a 76-year-old female patient, who received 2 g meropenem per day. On further investigation, they found that a direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG) and C3d, and reported the presence of meropenem-dependent antibodies in the patient’s serum [5].
The absence of drug-dependent antibody testing and bone marrow aspiration prevent us from drawing a firm conclusion regarding the mechanism of meropenem-induced pancytopenia in the present case. However, the hematological findings with the progressive development of thrombocytopenia, anemia, and then neutropenia suggest a possible mechanism of suppression of granulopoiesis or antibody-mediated destruction, as reported in recent studies [5, 6].
During hospitalization, the neonate received other medications, which have been reported to exert hematological effects. The baby initially received ampicillin, gentamicin, and fluconazole, and then received meropenem, colistin, vancomycin, and phenobarbital. However, severe thrombocytopenia developed on the sixth day of the first course of meropenem therapy, when the baby was also on colistin and fluconazole. This issue was resolved when meropenem was discontinued. During the second course of meropenem therapy, the baby again developed severe thrombocytopenia on the third day, while also receiving vancomycin, fluconazole, and phenobarbital. Phenobarbital-induced hematological abnormalities are reported in animal and adult studies [22, 23], and therefore it was discontinued on the sixth day. No seizures were observed but counts did not improve. However, the baby developed severe anemia and neutropenia while receiving fluconazole and meropenem only. After meropenem discontinuation, severe anemia and neutropenia showed a resolving trend for 3 days. Severe neutropenia resolved on the fourth day, and hemoglobin was reported at > 10 g/dl without transfusion on the seventh day of meropenem discontinuation, while fluconazole therapy was continued from the beginning until the 56th DOL, which further confirms the association of meropenem-induced hematological changes in this baby. It was also confirmed that the baby did not experience any additional infection even though she was not discharged on any antibiotic, which correlates with the fast recovery of blood counts after meropenem discontinuation.
Conclusions
In the present neonatal case, the gradual onset of hematological irregularities correlates with the commencement of meropenem therapy, and our observations are also verified by previously published evidence. The follow-up CBC count further established the resolution of pancytopenia after discontinuation of meropenem. Neonatal pancytopenia may lead to serious health complications; therefore, clinicians and pharmacists need to vigilantly monitor CBC counts in this vulnerable population, even when administering meropenem in septic doses for the recommended duration.
Patient perspective
From the perspective of the patient’s father, it was a rare case to have such kind of adverse events in a neonate with the normal treatment regimen. He was shared about all the events and he admired the team for the timely and effectively managing the issues and finally 100% recovery on the follow-ups.
Abbreviations
ANCAbsolute neutrophil count
CBCComplete blood count
DOLDay of life
CPAPContinuous positive airway pressure
TPNTotal parenteral nutrition
SIMVSynchronized intermittent mandatory ventilation
NECNecrotizing enterocolitis
PDAPatent ductus arteriosus
PPHNPersistent pulmonary hypertension of the newborn
CRPC-reactive protein
IDInfectious disease
Publisher's Note
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Acknowledgements
We acknowledge the kind support of Abdul Moiz Hussain for providing technical support in the process of final submission and language review. This study was conducted in the neonatal intensive care unit of Aga Khan University Hospital, Karachi, Pakistan.
Authors’ contributions
GA: Substantial contributions to the conception or design of the work. Performed the study, analysis, or interpretation of patient information. Major contributor in writing the manuscript. KH: Supervised the study and analyzed and interpreted the patient data regarding the hematological changes with therapy. Revised the work critically for important intellectual content. SS: Supervised the study and analyzed and interpreted the patient data regarding the hematological changes with therapy. Final approval of the version published. NM: Wrote the initial draft of the case report. AM: Co-wrote the initial draft. SI: data collection and interpretation. JI: data collection and interpretation. All authors read and approved the final manuscript.
Funding
No source of funding in the research.
Availability of data and materials
All data generated or analyzed during this study are included in the published article. The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Please contact the author for data requests.
Ethics approval and consent to participate
This case report was exempted from formal approval by the Ethical Review Committee, Aga Khan University Karachi, Pakistan.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | UNK, FROM THE SECOND DAY OF LIFE | DrugDosageText | CC BY | 33509295 | 18,915,789 | 2021-01-29 |
What was the outcome of reaction 'Anaemia neonatal'? | Meropenem-induced pancytopenia in a preterm neonate: a case report.
BACKGROUND
A post-marketing surveillance study has reported an association between meropenem use and the incidence of hematologic abnormalities, including leukopenia, thrombocytopenia, hemolysis, and neutropenia, but the precise incidence in neonates is unknown. Here, we report meropenem-induced pancytopenia in a preterm neonate.
METHODS
A preterm newborn Pakistani received intravenous meropenem 40 mg/kg every 8 hours to treat Klebsiella pneumoniae in blood cultures and suspected meningitis. The baby developed severe thrombocytopenia, with a platelet count of 22 × 103 cells/mm3, low hemoglobin level of 9.7 g/dl, and low absolute neutrophil count (ANC) of 816 cells/mm3 on days 3, 14, and 17 of meropenem therapy, respectively. Based on the blood culture and institutional guidelines, meropenem treatment was continued with monitoring and supportive care for a total of 19 days. After discontinuation of meropenem, the baby was monitored continuously for hematological changes, and low counts persisted for 3 days. ANC improved to > 1500 cells/mm3 on the fourth day, and the platelet count reached > 150 × 103 cells/mm3 for the first time on the seventh day of meropenem discontinuation. All subsequent complete blood count (CBC) reports showed improving trends. The baby was discharged on the 48th day of life (DOL), with follow-up monitoring of CBC. The baby was kept on iron supplements, and hemoglobin level of 11.2 g/dl was observed on the 59th DOL.
CONCLUSIONS
Neonatal pancytopenia may lead to serious health complications; therefore, clinicians and pharmacists need to vigilantly monitor CBC in this vulnerable population, even when administering meropenem in septic doses for the recommended duration.
Background
Pancytopenia is defined as reduced white blood cell (WBC) count, hemoglobin, and platelet count. Pancytopenia occurs when hemoglobin is < 13 g/dl in males and < 12 g/dl in females, absolute neutrophil count (ANC) is < 1500 cells/mm3, and platelet count is < 150 × 103 cells/mm3 [1]. Pancytopenia is considered severe if a patient experiences two or more of the following: hemoglobin < 7 g/dl, ANC < 500 cells/mm3, and platelet count < 50 × 103 cells/mm3. The mechanism underlying pancytopenia mainly involves bone marrow infiltration, bone marrow aplasia, and blood cell destruction that results in peripheral blood leakage [1]. Suppression of bone marrow varies widely in the pediatric population but may occur due to toxins, infection, or malignant cell infiltrates that can lead to hypocellular bone marrow function. Drug-induced pancytopenia is also a rare but secondary cause of bone marrow suppression due to direct bone marrow toxicity, immune-mediated (complement or antibody-mediated) cell destruction, and hapten formation, and directly affects myeloid precursors [2, 3]. An in vitro study of several beta-lactam antibiotics established the presence of well-differentiated myeloid cells and copious granulocyte precursors along with dose-dependent suppression of granulopoiesis [4]. Antibody-mediated hemolytic anemia and thrombocytopenia have also been established in meropenem-treated patients [5, 6]. Several medications can cause pancytopenia including chemotherapeutics, antiepileptics, antidepressants, and antibiotics [3, 5, 7]. A case–control epidemiological surveillance study was conducted over a follow-up period of 78.7 million person-years to assess the incidence of drug-induced agranulocytosis. Around 396 confirmed cases of acute neutropenia were observed, with an overall incidence of 3.5:1 million per year [8]. It was found that agranulocytosis clearly increased the risk of mortality, with a fatality rate of 9.1%. The most common drugs causing agranulocytosis were dipyrone (16%), beta-lactam antibiotics (12.0 %), ticlopidine (11.1%), antithyroid drugs (7.2%), and sulfonamide antibiotics (5.4%) [8].
Meropenem is one of the beta-lactam antibiotics that can cause serious and life-threatening neutropenia. It is a bactericidal broad-spectrum antibiotic with gram-positive, gram-negative, and anaerobic coverage, and is mainly used in the treatment of severe gram-negative infections in neonates including severe sepsis, meningitis, and complicated intra-abdominal infections such as necrotizing enterocolitis (NEC), one of the most common gastrointestinal emergencies and a major cause of morbidity and mortality in preterm neonates. For improved clinical outcomes, early recognition and aggressive management with broad-spectrum or combination antimicrobial agents is most often undertaken to treat NEC [9]. Because of its broad-spectrum activity, meropenem is an agent of great utility [10]. Based on the increasing trends of morbidity and mortality due to multidrug-resistant gram-negative bacterial infections in our neonatal intensive care unit (NICU), and following institutional guidelines, other antibiotics such as vancomycin and colistin are also used [11–13] after infectious disease (ID) consultation. The most common adverse effects of meropenem are constipation or diarrhea, nausea, vomiting, rashes, and diaper-area moniliasis in pediatric patients [14]. Some cases of meropenem-induced neutropenia have been reported [15]. However, no known case of meropenem-induced pancytopenia in neonates has yet been published. Here we report an event of meropenem-induced pancytopenia in a neonate admitted to the NICU of a tertiary-care hospital.
Case presentation
A newborn Pakistani baby was transferred to the intensive care unit due to prematurity, low birth weight, and intrauterine growth retardation. Her birth weight was 0.71 kg and APGAR scores were 3 at 1 minute and 4 at 5 minutes. Delivered by emergency C-section at 29 weeks due to raised blood pressure and fetal distress, she was initially kept on continuous positive airway pressure (CPAP) and given nothing through the mouth, and total parenteral nutrition (TPN) was started. Caffeine was loaded at 20 mg/kg and continued as the standard of care for apnea of prematurity. A prophylactic dose of 1 mg of vitamin K was given. During the first 24 hours, complete blood count (CBC) results were WBC of 18.3 × 103 cells/mm3, ANC of 1244 cells/mm3, platelet count of 166 × 103 cells/mm3, and hemoglobin of 17.8 g/dl. On the second day of life (DOL), ampicillin and gentamicin were started as empirical therapy, and the CBC report showed WBC 4 × 103 cells/mm3, ANC of 760 cells/mm3, platelet count of 152 × 103 cells/mm3, and hemoglobin of 15.9 g/dl. In addition, fluconazole was started as antifungal prophylaxis. The patient was given phototherapy. Chest X-ray and ultrasound of the head were performed, with normal findings. CPAP was tapered to high flow on merit, and blood culture was sent.
On the fourth DOL, the baby developed issues of severe respiratory distress and abdominal distension along with metabolic acidosis. She was intubated and kept on synchronized intermittent mandatory ventilation (SIMV) mode. The CBC results showed ANC of 912 cells/mm3, platelet count of 99 × 103 cells/mm3, and hemoglobin of 12.7 g/dl. Inotropic support was started, and antibiotics were escalated to meropenem 20 mg/kg every 12 hours, vancomycin 10 mg/kg once daily, and colistin at a loading dose of 5 mg/kg with a maintenance dose of 1.5 mg/kg every 12 hours. Blood culture showed no growth. After ID consult, vancomycin was discontinued on the third day and a decision was made to continue meropenem and colistin [11–13] to manage NEC and sepsis.
On the fifth DOL, echocardiogram was performed and showed patent ductus arteriosus (PDA) of 3 mm with severe persistent pulmonary hypertension of the newborn (PPHN). Acetaminophen was started for the next 5 days. On the sixth day of meropenem therapy, the platelet count dropped to 42 × 103 cells/mm3, treated in line with sepsis-associated thrombocytopenia [16], and managed by transfusion of 10 ml/kg platelet units [17]. Meropenem and colistin were discontinued on the eighth day of therapy, and trophic feeding was started. An echocardiogram was repeated on day 11, which showed a closed PDA and moderate PPHN. On the 18th DOL, the child was successfully extubated and kept on high-flow oxygen. There was slow progress in feeding.
On the 22nd DOL, the baby had tachycardia and an episode of 99.7 °F fever. Thus, septic workup was done and showed WBC count of 17.4 × 103 cells/mm3, ANC of 12,632.4 cells/mm3, and platelets of 203 × 103 cells/mm3. C-reactive protein (CRP) was 77 mg/l and renal function was normal (blood urea nitrogen [BUN] of 11 mg/dl and creatinine of 0.2 mg/dl). Meropenem was started in meningitic doses of 40 mg/kg every 8 hours [10] along with vancomycin 15 mg/kg every 12 hours.
In the microbiological investigation, urine and cerebrospinal fluid (CSF) cultures were found to be negative, but the blood culture was positive for Staphylococcus species (not aureus). Blood culture repeated after 48 hours was positive for carbapenem-sensitive Klebsiella pneumoniae. The baby was moved to the isolation room. On the 24th DOL, the baby developed severe thrombocytopenia, with a platelet count of 22 × 103 cells/mm3, managed with the transfusion of 10 ml/kg platelet units [17].
On the 25th DOL, an episode of generalized tonic-clonic fit occurred for which single-dose diazepam and a loading dose of phenobarbitone were given initially and then continued with maintenance doses of phenobarbitone. Due to significant metabolic acidosis and desaturation, the baby was re-intubated. After ID consult, meropenem was continued in meningitic doses and vancomycin was discontinued. SIMV and a central line were placed. TPN was started with nothing per oral status.
Blood gases were monitored, and the baby was extubated after 4 days and switched to CPAP. Phenobarbitone was discontinued after 6 days of therapy, and the baby was seizure-free through the remainder of the hospital stay. All repeat blood cultures were negative for any growth including CSF culture. The ID team was on board and decided to continue meropenem for a total of 14 days post-negative culture in septic doses of 20 mg/kg, and vancomycin was discontinued after 6 days. All repeated blood cultures obtained on the 27th and 30th DOL confirmed no pathogenic growth.
On the 33rd DOL, the CBC report showed WBC of 8.7 × 103 cells/mm3, ANC of 4576 cells/mm3, platelets of 78 × 103 cells/mm3, and hemoglobin of 10.8 g/dl. On the 36th DOL, the CBC report showed WBC of 5.1 × 103 cells/mm3, ANC of 2917 cells/mm3, platelets of 29 × 103 cells/mm3, and hemoglobin of 9.2 g/dl. The baby was managed for thrombocytopenia with platelet transfusion.
On the 37th DOL, hemoglobin dropped to 8.3 g/dl in the evening, and platelet count improved to 63 × 103 cells/mm3, WBC was 4.8 × 103 cells/mm3, and ANC was 1285 cells/mm3. On the 39th DOL, a marked reduction was observed in ANC to 816 cells/mm3, platelets of 38 × 103 cells/mm3, and hemoglobin of 8.3 g/dl, and the baby received blood transfusion to manage it. For constant issues, a hematological consult was taken and a decision was made to manage the baby symptomatically with 10 ml/kg platelet units at a platelet count < 50 [17] and 15 ml/kg packed cell transfusion at hemoglobin < 10 g/dl [18].
On the 40th DOL, meropenem was discontinued 14 days after negative culture (total of 19 days of meropenem therapy). On the same day the platelet count was 34 × 103 cells/mm3, ANC was 818 cells/mm3, and hemoglobin was 10.2 g/dl, and the baby was transfused to manage these issues. After discontinuation of meropenem, the baby was continuously monitored for hematological changes, and low counts persisted for 3 days. Improved ANC of > 1500 cells/mm3 was reported on the fourth day, and platelet count of > 150 × 103 cells/mm3 was reported for the first time on the sixth day of meropenem discontinuation, but hemoglobin was still low (Fig 1). CPAP was tapered gradually to nasal prongs. The peripherally inserted central catheter was removed, and orogastric (OG) tube feeding was commenced. The baby was discharged on the 48th DOL on iron supplements with follow-up monitoring of CBC. Hemoglobin level of 11.2 g/dl was found on the 59th DOL.Fig. 1. Hematological changes and timing of medication during hospitalization
Discussion
Drug-induced pancytopenia is a rare hematological problem in neonatal clinical practices, evaluated based on a complete underlying pathological history, physical examination, and vigilant interpretation of biochemical, radiological, histopathological, and hematological findings [19]. Concerns have been raised about hematological adverse effects of several beta-lactamase inhibitors [8]. This neonatal case documents meropenem-induced pancytopenia and emphasizes cautious laboratory monitoring for patients receiving meropenem therapy.
Sepsis is another known etiology of pancytopenia. Although the neonate in the present case had a blood culture positive for K. pneumoniae, the results of all repeated blood cultures were negative, showing the resolution of sepsis. Van Tuyl et al. [20] also reported a case of a neonate receiving meropenem in meningitic doses of 40 mg/kg/day to treat meropenem-susceptible Enterobacter cloacae in blood culture. The baby developed meropenem-induced neutropenia on the 13th day of therapy, with ANC of 288 cells/mm3. The decision was made to discontinue meropenem on the 19th day of therapy instead of the initially planned 21 days. In the present case, the baby continued to receive meropenem treatment and was managed for hematological problems based on institutional guidelines and culture sensitivity. Initially, hematological changes were not considered as directly meropenem-induced.
Recently published reports also support the notion of carbapenem-induced hematological disorders. A case report by Estella and colleagues [21] described meropenem-induced pancytopenia in a 3-year-old patient at 100 mg/kg given every 8 hours to manage the regrowth of meropenem-sensitive Morganella morganii in CSF cultures. Huang et al. [6] reported a case of meropenem-induced immune thrombocytopenia in a 59-year-old patient, by detecting meropenem-dependent platelet antibodies and platelet count recovery after discontinuation of meropenem. Oka et al. [5] reported the development of severe anemia with clinical signs in a 76-year-old female patient, who received 2 g meropenem per day. On further investigation, they found that a direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG) and C3d, and reported the presence of meropenem-dependent antibodies in the patient’s serum [5].
The absence of drug-dependent antibody testing and bone marrow aspiration prevent us from drawing a firm conclusion regarding the mechanism of meropenem-induced pancytopenia in the present case. However, the hematological findings with the progressive development of thrombocytopenia, anemia, and then neutropenia suggest a possible mechanism of suppression of granulopoiesis or antibody-mediated destruction, as reported in recent studies [5, 6].
During hospitalization, the neonate received other medications, which have been reported to exert hematological effects. The baby initially received ampicillin, gentamicin, and fluconazole, and then received meropenem, colistin, vancomycin, and phenobarbital. However, severe thrombocytopenia developed on the sixth day of the first course of meropenem therapy, when the baby was also on colistin and fluconazole. This issue was resolved when meropenem was discontinued. During the second course of meropenem therapy, the baby again developed severe thrombocytopenia on the third day, while also receiving vancomycin, fluconazole, and phenobarbital. Phenobarbital-induced hematological abnormalities are reported in animal and adult studies [22, 23], and therefore it was discontinued on the sixth day. No seizures were observed but counts did not improve. However, the baby developed severe anemia and neutropenia while receiving fluconazole and meropenem only. After meropenem discontinuation, severe anemia and neutropenia showed a resolving trend for 3 days. Severe neutropenia resolved on the fourth day, and hemoglobin was reported at > 10 g/dl without transfusion on the seventh day of meropenem discontinuation, while fluconazole therapy was continued from the beginning until the 56th DOL, which further confirms the association of meropenem-induced hematological changes in this baby. It was also confirmed that the baby did not experience any additional infection even though she was not discharged on any antibiotic, which correlates with the fast recovery of blood counts after meropenem discontinuation.
Conclusions
In the present neonatal case, the gradual onset of hematological irregularities correlates with the commencement of meropenem therapy, and our observations are also verified by previously published evidence. The follow-up CBC count further established the resolution of pancytopenia after discontinuation of meropenem. Neonatal pancytopenia may lead to serious health complications; therefore, clinicians and pharmacists need to vigilantly monitor CBC counts in this vulnerable population, even when administering meropenem in septic doses for the recommended duration.
Patient perspective
From the perspective of the patient’s father, it was a rare case to have such kind of adverse events in a neonate with the normal treatment regimen. He was shared about all the events and he admired the team for the timely and effectively managing the issues and finally 100% recovery on the follow-ups.
Abbreviations
ANCAbsolute neutrophil count
CBCComplete blood count
DOLDay of life
CPAPContinuous positive airway pressure
TPNTotal parenteral nutrition
SIMVSynchronized intermittent mandatory ventilation
NECNecrotizing enterocolitis
PDAPatent ductus arteriosus
PPHNPersistent pulmonary hypertension of the newborn
CRPC-reactive protein
IDInfectious disease
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We acknowledge the kind support of Abdul Moiz Hussain for providing technical support in the process of final submission and language review. This study was conducted in the neonatal intensive care unit of Aga Khan University Hospital, Karachi, Pakistan.
Authors’ contributions
GA: Substantial contributions to the conception or design of the work. Performed the study, analysis, or interpretation of patient information. Major contributor in writing the manuscript. KH: Supervised the study and analyzed and interpreted the patient data regarding the hematological changes with therapy. Revised the work critically for important intellectual content. SS: Supervised the study and analyzed and interpreted the patient data regarding the hematological changes with therapy. Final approval of the version published. NM: Wrote the initial draft of the case report. AM: Co-wrote the initial draft. SI: data collection and interpretation. JI: data collection and interpretation. All authors read and approved the final manuscript.
Funding
No source of funding in the research.
Availability of data and materials
All data generated or analyzed during this study are included in the published article. The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Please contact the author for data requests.
Ethics approval and consent to participate
This case report was exempted from formal approval by the Ethical Review Committee, Aga Khan University Karachi, Pakistan.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33509295 | 18,915,789 | 2021-01-29 |
What was the outcome of reaction 'Neutropenia neonatal'? | Meropenem-induced pancytopenia in a preterm neonate: a case report.
BACKGROUND
A post-marketing surveillance study has reported an association between meropenem use and the incidence of hematologic abnormalities, including leukopenia, thrombocytopenia, hemolysis, and neutropenia, but the precise incidence in neonates is unknown. Here, we report meropenem-induced pancytopenia in a preterm neonate.
METHODS
A preterm newborn Pakistani received intravenous meropenem 40 mg/kg every 8 hours to treat Klebsiella pneumoniae in blood cultures and suspected meningitis. The baby developed severe thrombocytopenia, with a platelet count of 22 × 103 cells/mm3, low hemoglobin level of 9.7 g/dl, and low absolute neutrophil count (ANC) of 816 cells/mm3 on days 3, 14, and 17 of meropenem therapy, respectively. Based on the blood culture and institutional guidelines, meropenem treatment was continued with monitoring and supportive care for a total of 19 days. After discontinuation of meropenem, the baby was monitored continuously for hematological changes, and low counts persisted for 3 days. ANC improved to > 1500 cells/mm3 on the fourth day, and the platelet count reached > 150 × 103 cells/mm3 for the first time on the seventh day of meropenem discontinuation. All subsequent complete blood count (CBC) reports showed improving trends. The baby was discharged on the 48th day of life (DOL), with follow-up monitoring of CBC. The baby was kept on iron supplements, and hemoglobin level of 11.2 g/dl was observed on the 59th DOL.
CONCLUSIONS
Neonatal pancytopenia may lead to serious health complications; therefore, clinicians and pharmacists need to vigilantly monitor CBC in this vulnerable population, even when administering meropenem in septic doses for the recommended duration.
Background
Pancytopenia is defined as reduced white blood cell (WBC) count, hemoglobin, and platelet count. Pancytopenia occurs when hemoglobin is < 13 g/dl in males and < 12 g/dl in females, absolute neutrophil count (ANC) is < 1500 cells/mm3, and platelet count is < 150 × 103 cells/mm3 [1]. Pancytopenia is considered severe if a patient experiences two or more of the following: hemoglobin < 7 g/dl, ANC < 500 cells/mm3, and platelet count < 50 × 103 cells/mm3. The mechanism underlying pancytopenia mainly involves bone marrow infiltration, bone marrow aplasia, and blood cell destruction that results in peripheral blood leakage [1]. Suppression of bone marrow varies widely in the pediatric population but may occur due to toxins, infection, or malignant cell infiltrates that can lead to hypocellular bone marrow function. Drug-induced pancytopenia is also a rare but secondary cause of bone marrow suppression due to direct bone marrow toxicity, immune-mediated (complement or antibody-mediated) cell destruction, and hapten formation, and directly affects myeloid precursors [2, 3]. An in vitro study of several beta-lactam antibiotics established the presence of well-differentiated myeloid cells and copious granulocyte precursors along with dose-dependent suppression of granulopoiesis [4]. Antibody-mediated hemolytic anemia and thrombocytopenia have also been established in meropenem-treated patients [5, 6]. Several medications can cause pancytopenia including chemotherapeutics, antiepileptics, antidepressants, and antibiotics [3, 5, 7]. A case–control epidemiological surveillance study was conducted over a follow-up period of 78.7 million person-years to assess the incidence of drug-induced agranulocytosis. Around 396 confirmed cases of acute neutropenia were observed, with an overall incidence of 3.5:1 million per year [8]. It was found that agranulocytosis clearly increased the risk of mortality, with a fatality rate of 9.1%. The most common drugs causing agranulocytosis were dipyrone (16%), beta-lactam antibiotics (12.0 %), ticlopidine (11.1%), antithyroid drugs (7.2%), and sulfonamide antibiotics (5.4%) [8].
Meropenem is one of the beta-lactam antibiotics that can cause serious and life-threatening neutropenia. It is a bactericidal broad-spectrum antibiotic with gram-positive, gram-negative, and anaerobic coverage, and is mainly used in the treatment of severe gram-negative infections in neonates including severe sepsis, meningitis, and complicated intra-abdominal infections such as necrotizing enterocolitis (NEC), one of the most common gastrointestinal emergencies and a major cause of morbidity and mortality in preterm neonates. For improved clinical outcomes, early recognition and aggressive management with broad-spectrum or combination antimicrobial agents is most often undertaken to treat NEC [9]. Because of its broad-spectrum activity, meropenem is an agent of great utility [10]. Based on the increasing trends of morbidity and mortality due to multidrug-resistant gram-negative bacterial infections in our neonatal intensive care unit (NICU), and following institutional guidelines, other antibiotics such as vancomycin and colistin are also used [11–13] after infectious disease (ID) consultation. The most common adverse effects of meropenem are constipation or diarrhea, nausea, vomiting, rashes, and diaper-area moniliasis in pediatric patients [14]. Some cases of meropenem-induced neutropenia have been reported [15]. However, no known case of meropenem-induced pancytopenia in neonates has yet been published. Here we report an event of meropenem-induced pancytopenia in a neonate admitted to the NICU of a tertiary-care hospital.
Case presentation
A newborn Pakistani baby was transferred to the intensive care unit due to prematurity, low birth weight, and intrauterine growth retardation. Her birth weight was 0.71 kg and APGAR scores were 3 at 1 minute and 4 at 5 minutes. Delivered by emergency C-section at 29 weeks due to raised blood pressure and fetal distress, she was initially kept on continuous positive airway pressure (CPAP) and given nothing through the mouth, and total parenteral nutrition (TPN) was started. Caffeine was loaded at 20 mg/kg and continued as the standard of care for apnea of prematurity. A prophylactic dose of 1 mg of vitamin K was given. During the first 24 hours, complete blood count (CBC) results were WBC of 18.3 × 103 cells/mm3, ANC of 1244 cells/mm3, platelet count of 166 × 103 cells/mm3, and hemoglobin of 17.8 g/dl. On the second day of life (DOL), ampicillin and gentamicin were started as empirical therapy, and the CBC report showed WBC 4 × 103 cells/mm3, ANC of 760 cells/mm3, platelet count of 152 × 103 cells/mm3, and hemoglobin of 15.9 g/dl. In addition, fluconazole was started as antifungal prophylaxis. The patient was given phototherapy. Chest X-ray and ultrasound of the head were performed, with normal findings. CPAP was tapered to high flow on merit, and blood culture was sent.
On the fourth DOL, the baby developed issues of severe respiratory distress and abdominal distension along with metabolic acidosis. She was intubated and kept on synchronized intermittent mandatory ventilation (SIMV) mode. The CBC results showed ANC of 912 cells/mm3, platelet count of 99 × 103 cells/mm3, and hemoglobin of 12.7 g/dl. Inotropic support was started, and antibiotics were escalated to meropenem 20 mg/kg every 12 hours, vancomycin 10 mg/kg once daily, and colistin at a loading dose of 5 mg/kg with a maintenance dose of 1.5 mg/kg every 12 hours. Blood culture showed no growth. After ID consult, vancomycin was discontinued on the third day and a decision was made to continue meropenem and colistin [11–13] to manage NEC and sepsis.
On the fifth DOL, echocardiogram was performed and showed patent ductus arteriosus (PDA) of 3 mm with severe persistent pulmonary hypertension of the newborn (PPHN). Acetaminophen was started for the next 5 days. On the sixth day of meropenem therapy, the platelet count dropped to 42 × 103 cells/mm3, treated in line with sepsis-associated thrombocytopenia [16], and managed by transfusion of 10 ml/kg platelet units [17]. Meropenem and colistin were discontinued on the eighth day of therapy, and trophic feeding was started. An echocardiogram was repeated on day 11, which showed a closed PDA and moderate PPHN. On the 18th DOL, the child was successfully extubated and kept on high-flow oxygen. There was slow progress in feeding.
On the 22nd DOL, the baby had tachycardia and an episode of 99.7 °F fever. Thus, septic workup was done and showed WBC count of 17.4 × 103 cells/mm3, ANC of 12,632.4 cells/mm3, and platelets of 203 × 103 cells/mm3. C-reactive protein (CRP) was 77 mg/l and renal function was normal (blood urea nitrogen [BUN] of 11 mg/dl and creatinine of 0.2 mg/dl). Meropenem was started in meningitic doses of 40 mg/kg every 8 hours [10] along with vancomycin 15 mg/kg every 12 hours.
In the microbiological investigation, urine and cerebrospinal fluid (CSF) cultures were found to be negative, but the blood culture was positive for Staphylococcus species (not aureus). Blood culture repeated after 48 hours was positive for carbapenem-sensitive Klebsiella pneumoniae. The baby was moved to the isolation room. On the 24th DOL, the baby developed severe thrombocytopenia, with a platelet count of 22 × 103 cells/mm3, managed with the transfusion of 10 ml/kg platelet units [17].
On the 25th DOL, an episode of generalized tonic-clonic fit occurred for which single-dose diazepam and a loading dose of phenobarbitone were given initially and then continued with maintenance doses of phenobarbitone. Due to significant metabolic acidosis and desaturation, the baby was re-intubated. After ID consult, meropenem was continued in meningitic doses and vancomycin was discontinued. SIMV and a central line were placed. TPN was started with nothing per oral status.
Blood gases were monitored, and the baby was extubated after 4 days and switched to CPAP. Phenobarbitone was discontinued after 6 days of therapy, and the baby was seizure-free through the remainder of the hospital stay. All repeat blood cultures were negative for any growth including CSF culture. The ID team was on board and decided to continue meropenem for a total of 14 days post-negative culture in septic doses of 20 mg/kg, and vancomycin was discontinued after 6 days. All repeated blood cultures obtained on the 27th and 30th DOL confirmed no pathogenic growth.
On the 33rd DOL, the CBC report showed WBC of 8.7 × 103 cells/mm3, ANC of 4576 cells/mm3, platelets of 78 × 103 cells/mm3, and hemoglobin of 10.8 g/dl. On the 36th DOL, the CBC report showed WBC of 5.1 × 103 cells/mm3, ANC of 2917 cells/mm3, platelets of 29 × 103 cells/mm3, and hemoglobin of 9.2 g/dl. The baby was managed for thrombocytopenia with platelet transfusion.
On the 37th DOL, hemoglobin dropped to 8.3 g/dl in the evening, and platelet count improved to 63 × 103 cells/mm3, WBC was 4.8 × 103 cells/mm3, and ANC was 1285 cells/mm3. On the 39th DOL, a marked reduction was observed in ANC to 816 cells/mm3, platelets of 38 × 103 cells/mm3, and hemoglobin of 8.3 g/dl, and the baby received blood transfusion to manage it. For constant issues, a hematological consult was taken and a decision was made to manage the baby symptomatically with 10 ml/kg platelet units at a platelet count < 50 [17] and 15 ml/kg packed cell transfusion at hemoglobin < 10 g/dl [18].
On the 40th DOL, meropenem was discontinued 14 days after negative culture (total of 19 days of meropenem therapy). On the same day the platelet count was 34 × 103 cells/mm3, ANC was 818 cells/mm3, and hemoglobin was 10.2 g/dl, and the baby was transfused to manage these issues. After discontinuation of meropenem, the baby was continuously monitored for hematological changes, and low counts persisted for 3 days. Improved ANC of > 1500 cells/mm3 was reported on the fourth day, and platelet count of > 150 × 103 cells/mm3 was reported for the first time on the sixth day of meropenem discontinuation, but hemoglobin was still low (Fig 1). CPAP was tapered gradually to nasal prongs. The peripherally inserted central catheter was removed, and orogastric (OG) tube feeding was commenced. The baby was discharged on the 48th DOL on iron supplements with follow-up monitoring of CBC. Hemoglobin level of 11.2 g/dl was found on the 59th DOL.Fig. 1. Hematological changes and timing of medication during hospitalization
Discussion
Drug-induced pancytopenia is a rare hematological problem in neonatal clinical practices, evaluated based on a complete underlying pathological history, physical examination, and vigilant interpretation of biochemical, radiological, histopathological, and hematological findings [19]. Concerns have been raised about hematological adverse effects of several beta-lactamase inhibitors [8]. This neonatal case documents meropenem-induced pancytopenia and emphasizes cautious laboratory monitoring for patients receiving meropenem therapy.
Sepsis is another known etiology of pancytopenia. Although the neonate in the present case had a blood culture positive for K. pneumoniae, the results of all repeated blood cultures were negative, showing the resolution of sepsis. Van Tuyl et al. [20] also reported a case of a neonate receiving meropenem in meningitic doses of 40 mg/kg/day to treat meropenem-susceptible Enterobacter cloacae in blood culture. The baby developed meropenem-induced neutropenia on the 13th day of therapy, with ANC of 288 cells/mm3. The decision was made to discontinue meropenem on the 19th day of therapy instead of the initially planned 21 days. In the present case, the baby continued to receive meropenem treatment and was managed for hematological problems based on institutional guidelines and culture sensitivity. Initially, hematological changes were not considered as directly meropenem-induced.
Recently published reports also support the notion of carbapenem-induced hematological disorders. A case report by Estella and colleagues [21] described meropenem-induced pancytopenia in a 3-year-old patient at 100 mg/kg given every 8 hours to manage the regrowth of meropenem-sensitive Morganella morganii in CSF cultures. Huang et al. [6] reported a case of meropenem-induced immune thrombocytopenia in a 59-year-old patient, by detecting meropenem-dependent platelet antibodies and platelet count recovery after discontinuation of meropenem. Oka et al. [5] reported the development of severe anemia with clinical signs in a 76-year-old female patient, who received 2 g meropenem per day. On further investigation, they found that a direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG) and C3d, and reported the presence of meropenem-dependent antibodies in the patient’s serum [5].
The absence of drug-dependent antibody testing and bone marrow aspiration prevent us from drawing a firm conclusion regarding the mechanism of meropenem-induced pancytopenia in the present case. However, the hematological findings with the progressive development of thrombocytopenia, anemia, and then neutropenia suggest a possible mechanism of suppression of granulopoiesis or antibody-mediated destruction, as reported in recent studies [5, 6].
During hospitalization, the neonate received other medications, which have been reported to exert hematological effects. The baby initially received ampicillin, gentamicin, and fluconazole, and then received meropenem, colistin, vancomycin, and phenobarbital. However, severe thrombocytopenia developed on the sixth day of the first course of meropenem therapy, when the baby was also on colistin and fluconazole. This issue was resolved when meropenem was discontinued. During the second course of meropenem therapy, the baby again developed severe thrombocytopenia on the third day, while also receiving vancomycin, fluconazole, and phenobarbital. Phenobarbital-induced hematological abnormalities are reported in animal and adult studies [22, 23], and therefore it was discontinued on the sixth day. No seizures were observed but counts did not improve. However, the baby developed severe anemia and neutropenia while receiving fluconazole and meropenem only. After meropenem discontinuation, severe anemia and neutropenia showed a resolving trend for 3 days. Severe neutropenia resolved on the fourth day, and hemoglobin was reported at > 10 g/dl without transfusion on the seventh day of meropenem discontinuation, while fluconazole therapy was continued from the beginning until the 56th DOL, which further confirms the association of meropenem-induced hematological changes in this baby. It was also confirmed that the baby did not experience any additional infection even though she was not discharged on any antibiotic, which correlates with the fast recovery of blood counts after meropenem discontinuation.
Conclusions
In the present neonatal case, the gradual onset of hematological irregularities correlates with the commencement of meropenem therapy, and our observations are also verified by previously published evidence. The follow-up CBC count further established the resolution of pancytopenia after discontinuation of meropenem. Neonatal pancytopenia may lead to serious health complications; therefore, clinicians and pharmacists need to vigilantly monitor CBC counts in this vulnerable population, even when administering meropenem in septic doses for the recommended duration.
Patient perspective
From the perspective of the patient’s father, it was a rare case to have such kind of adverse events in a neonate with the normal treatment regimen. He was shared about all the events and he admired the team for the timely and effectively managing the issues and finally 100% recovery on the follow-ups.
Abbreviations
ANCAbsolute neutrophil count
CBCComplete blood count
DOLDay of life
CPAPContinuous positive airway pressure
TPNTotal parenteral nutrition
SIMVSynchronized intermittent mandatory ventilation
NECNecrotizing enterocolitis
PDAPatent ductus arteriosus
PPHNPersistent pulmonary hypertension of the newborn
CRPC-reactive protein
IDInfectious disease
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We acknowledge the kind support of Abdul Moiz Hussain for providing technical support in the process of final submission and language review. This study was conducted in the neonatal intensive care unit of Aga Khan University Hospital, Karachi, Pakistan.
Authors’ contributions
GA: Substantial contributions to the conception or design of the work. Performed the study, analysis, or interpretation of patient information. Major contributor in writing the manuscript. KH: Supervised the study and analyzed and interpreted the patient data regarding the hematological changes with therapy. Revised the work critically for important intellectual content. SS: Supervised the study and analyzed and interpreted the patient data regarding the hematological changes with therapy. Final approval of the version published. NM: Wrote the initial draft of the case report. AM: Co-wrote the initial draft. SI: data collection and interpretation. JI: data collection and interpretation. All authors read and approved the final manuscript.
Funding
No source of funding in the research.
Availability of data and materials
All data generated or analyzed during this study are included in the published article. The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Please contact the author for data requests.
Ethics approval and consent to participate
This case report was exempted from formal approval by the Ethical Review Committee, Aga Khan University Karachi, Pakistan.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33509295 | 18,915,789 | 2021-01-29 |
What was the outcome of reaction 'Pancytopenia'? | Meropenem-induced pancytopenia in a preterm neonate: a case report.
BACKGROUND
A post-marketing surveillance study has reported an association between meropenem use and the incidence of hematologic abnormalities, including leukopenia, thrombocytopenia, hemolysis, and neutropenia, but the precise incidence in neonates is unknown. Here, we report meropenem-induced pancytopenia in a preterm neonate.
METHODS
A preterm newborn Pakistani received intravenous meropenem 40 mg/kg every 8 hours to treat Klebsiella pneumoniae in blood cultures and suspected meningitis. The baby developed severe thrombocytopenia, with a platelet count of 22 × 103 cells/mm3, low hemoglobin level of 9.7 g/dl, and low absolute neutrophil count (ANC) of 816 cells/mm3 on days 3, 14, and 17 of meropenem therapy, respectively. Based on the blood culture and institutional guidelines, meropenem treatment was continued with monitoring and supportive care for a total of 19 days. After discontinuation of meropenem, the baby was monitored continuously for hematological changes, and low counts persisted for 3 days. ANC improved to > 1500 cells/mm3 on the fourth day, and the platelet count reached > 150 × 103 cells/mm3 for the first time on the seventh day of meropenem discontinuation. All subsequent complete blood count (CBC) reports showed improving trends. The baby was discharged on the 48th day of life (DOL), with follow-up monitoring of CBC. The baby was kept on iron supplements, and hemoglobin level of 11.2 g/dl was observed on the 59th DOL.
CONCLUSIONS
Neonatal pancytopenia may lead to serious health complications; therefore, clinicians and pharmacists need to vigilantly monitor CBC in this vulnerable population, even when administering meropenem in septic doses for the recommended duration.
Background
Pancytopenia is defined as reduced white blood cell (WBC) count, hemoglobin, and platelet count. Pancytopenia occurs when hemoglobin is < 13 g/dl in males and < 12 g/dl in females, absolute neutrophil count (ANC) is < 1500 cells/mm3, and platelet count is < 150 × 103 cells/mm3 [1]. Pancytopenia is considered severe if a patient experiences two or more of the following: hemoglobin < 7 g/dl, ANC < 500 cells/mm3, and platelet count < 50 × 103 cells/mm3. The mechanism underlying pancytopenia mainly involves bone marrow infiltration, bone marrow aplasia, and blood cell destruction that results in peripheral blood leakage [1]. Suppression of bone marrow varies widely in the pediatric population but may occur due to toxins, infection, or malignant cell infiltrates that can lead to hypocellular bone marrow function. Drug-induced pancytopenia is also a rare but secondary cause of bone marrow suppression due to direct bone marrow toxicity, immune-mediated (complement or antibody-mediated) cell destruction, and hapten formation, and directly affects myeloid precursors [2, 3]. An in vitro study of several beta-lactam antibiotics established the presence of well-differentiated myeloid cells and copious granulocyte precursors along with dose-dependent suppression of granulopoiesis [4]. Antibody-mediated hemolytic anemia and thrombocytopenia have also been established in meropenem-treated patients [5, 6]. Several medications can cause pancytopenia including chemotherapeutics, antiepileptics, antidepressants, and antibiotics [3, 5, 7]. A case–control epidemiological surveillance study was conducted over a follow-up period of 78.7 million person-years to assess the incidence of drug-induced agranulocytosis. Around 396 confirmed cases of acute neutropenia were observed, with an overall incidence of 3.5:1 million per year [8]. It was found that agranulocytosis clearly increased the risk of mortality, with a fatality rate of 9.1%. The most common drugs causing agranulocytosis were dipyrone (16%), beta-lactam antibiotics (12.0 %), ticlopidine (11.1%), antithyroid drugs (7.2%), and sulfonamide antibiotics (5.4%) [8].
Meropenem is one of the beta-lactam antibiotics that can cause serious and life-threatening neutropenia. It is a bactericidal broad-spectrum antibiotic with gram-positive, gram-negative, and anaerobic coverage, and is mainly used in the treatment of severe gram-negative infections in neonates including severe sepsis, meningitis, and complicated intra-abdominal infections such as necrotizing enterocolitis (NEC), one of the most common gastrointestinal emergencies and a major cause of morbidity and mortality in preterm neonates. For improved clinical outcomes, early recognition and aggressive management with broad-spectrum or combination antimicrobial agents is most often undertaken to treat NEC [9]. Because of its broad-spectrum activity, meropenem is an agent of great utility [10]. Based on the increasing trends of morbidity and mortality due to multidrug-resistant gram-negative bacterial infections in our neonatal intensive care unit (NICU), and following institutional guidelines, other antibiotics such as vancomycin and colistin are also used [11–13] after infectious disease (ID) consultation. The most common adverse effects of meropenem are constipation or diarrhea, nausea, vomiting, rashes, and diaper-area moniliasis in pediatric patients [14]. Some cases of meropenem-induced neutropenia have been reported [15]. However, no known case of meropenem-induced pancytopenia in neonates has yet been published. Here we report an event of meropenem-induced pancytopenia in a neonate admitted to the NICU of a tertiary-care hospital.
Case presentation
A newborn Pakistani baby was transferred to the intensive care unit due to prematurity, low birth weight, and intrauterine growth retardation. Her birth weight was 0.71 kg and APGAR scores were 3 at 1 minute and 4 at 5 minutes. Delivered by emergency C-section at 29 weeks due to raised blood pressure and fetal distress, she was initially kept on continuous positive airway pressure (CPAP) and given nothing through the mouth, and total parenteral nutrition (TPN) was started. Caffeine was loaded at 20 mg/kg and continued as the standard of care for apnea of prematurity. A prophylactic dose of 1 mg of vitamin K was given. During the first 24 hours, complete blood count (CBC) results were WBC of 18.3 × 103 cells/mm3, ANC of 1244 cells/mm3, platelet count of 166 × 103 cells/mm3, and hemoglobin of 17.8 g/dl. On the second day of life (DOL), ampicillin and gentamicin were started as empirical therapy, and the CBC report showed WBC 4 × 103 cells/mm3, ANC of 760 cells/mm3, platelet count of 152 × 103 cells/mm3, and hemoglobin of 15.9 g/dl. In addition, fluconazole was started as antifungal prophylaxis. The patient was given phototherapy. Chest X-ray and ultrasound of the head were performed, with normal findings. CPAP was tapered to high flow on merit, and blood culture was sent.
On the fourth DOL, the baby developed issues of severe respiratory distress and abdominal distension along with metabolic acidosis. She was intubated and kept on synchronized intermittent mandatory ventilation (SIMV) mode. The CBC results showed ANC of 912 cells/mm3, platelet count of 99 × 103 cells/mm3, and hemoglobin of 12.7 g/dl. Inotropic support was started, and antibiotics were escalated to meropenem 20 mg/kg every 12 hours, vancomycin 10 mg/kg once daily, and colistin at a loading dose of 5 mg/kg with a maintenance dose of 1.5 mg/kg every 12 hours. Blood culture showed no growth. After ID consult, vancomycin was discontinued on the third day and a decision was made to continue meropenem and colistin [11–13] to manage NEC and sepsis.
On the fifth DOL, echocardiogram was performed and showed patent ductus arteriosus (PDA) of 3 mm with severe persistent pulmonary hypertension of the newborn (PPHN). Acetaminophen was started for the next 5 days. On the sixth day of meropenem therapy, the platelet count dropped to 42 × 103 cells/mm3, treated in line with sepsis-associated thrombocytopenia [16], and managed by transfusion of 10 ml/kg platelet units [17]. Meropenem and colistin were discontinued on the eighth day of therapy, and trophic feeding was started. An echocardiogram was repeated on day 11, which showed a closed PDA and moderate PPHN. On the 18th DOL, the child was successfully extubated and kept on high-flow oxygen. There was slow progress in feeding.
On the 22nd DOL, the baby had tachycardia and an episode of 99.7 °F fever. Thus, septic workup was done and showed WBC count of 17.4 × 103 cells/mm3, ANC of 12,632.4 cells/mm3, and platelets of 203 × 103 cells/mm3. C-reactive protein (CRP) was 77 mg/l and renal function was normal (blood urea nitrogen [BUN] of 11 mg/dl and creatinine of 0.2 mg/dl). Meropenem was started in meningitic doses of 40 mg/kg every 8 hours [10] along with vancomycin 15 mg/kg every 12 hours.
In the microbiological investigation, urine and cerebrospinal fluid (CSF) cultures were found to be negative, but the blood culture was positive for Staphylococcus species (not aureus). Blood culture repeated after 48 hours was positive for carbapenem-sensitive Klebsiella pneumoniae. The baby was moved to the isolation room. On the 24th DOL, the baby developed severe thrombocytopenia, with a platelet count of 22 × 103 cells/mm3, managed with the transfusion of 10 ml/kg platelet units [17].
On the 25th DOL, an episode of generalized tonic-clonic fit occurred for which single-dose diazepam and a loading dose of phenobarbitone were given initially and then continued with maintenance doses of phenobarbitone. Due to significant metabolic acidosis and desaturation, the baby was re-intubated. After ID consult, meropenem was continued in meningitic doses and vancomycin was discontinued. SIMV and a central line were placed. TPN was started with nothing per oral status.
Blood gases were monitored, and the baby was extubated after 4 days and switched to CPAP. Phenobarbitone was discontinued after 6 days of therapy, and the baby was seizure-free through the remainder of the hospital stay. All repeat blood cultures were negative for any growth including CSF culture. The ID team was on board and decided to continue meropenem for a total of 14 days post-negative culture in septic doses of 20 mg/kg, and vancomycin was discontinued after 6 days. All repeated blood cultures obtained on the 27th and 30th DOL confirmed no pathogenic growth.
On the 33rd DOL, the CBC report showed WBC of 8.7 × 103 cells/mm3, ANC of 4576 cells/mm3, platelets of 78 × 103 cells/mm3, and hemoglobin of 10.8 g/dl. On the 36th DOL, the CBC report showed WBC of 5.1 × 103 cells/mm3, ANC of 2917 cells/mm3, platelets of 29 × 103 cells/mm3, and hemoglobin of 9.2 g/dl. The baby was managed for thrombocytopenia with platelet transfusion.
On the 37th DOL, hemoglobin dropped to 8.3 g/dl in the evening, and platelet count improved to 63 × 103 cells/mm3, WBC was 4.8 × 103 cells/mm3, and ANC was 1285 cells/mm3. On the 39th DOL, a marked reduction was observed in ANC to 816 cells/mm3, platelets of 38 × 103 cells/mm3, and hemoglobin of 8.3 g/dl, and the baby received blood transfusion to manage it. For constant issues, a hematological consult was taken and a decision was made to manage the baby symptomatically with 10 ml/kg platelet units at a platelet count < 50 [17] and 15 ml/kg packed cell transfusion at hemoglobin < 10 g/dl [18].
On the 40th DOL, meropenem was discontinued 14 days after negative culture (total of 19 days of meropenem therapy). On the same day the platelet count was 34 × 103 cells/mm3, ANC was 818 cells/mm3, and hemoglobin was 10.2 g/dl, and the baby was transfused to manage these issues. After discontinuation of meropenem, the baby was continuously monitored for hematological changes, and low counts persisted for 3 days. Improved ANC of > 1500 cells/mm3 was reported on the fourth day, and platelet count of > 150 × 103 cells/mm3 was reported for the first time on the sixth day of meropenem discontinuation, but hemoglobin was still low (Fig 1). CPAP was tapered gradually to nasal prongs. The peripherally inserted central catheter was removed, and orogastric (OG) tube feeding was commenced. The baby was discharged on the 48th DOL on iron supplements with follow-up monitoring of CBC. Hemoglobin level of 11.2 g/dl was found on the 59th DOL.Fig. 1. Hematological changes and timing of medication during hospitalization
Discussion
Drug-induced pancytopenia is a rare hematological problem in neonatal clinical practices, evaluated based on a complete underlying pathological history, physical examination, and vigilant interpretation of biochemical, radiological, histopathological, and hematological findings [19]. Concerns have been raised about hematological adverse effects of several beta-lactamase inhibitors [8]. This neonatal case documents meropenem-induced pancytopenia and emphasizes cautious laboratory monitoring for patients receiving meropenem therapy.
Sepsis is another known etiology of pancytopenia. Although the neonate in the present case had a blood culture positive for K. pneumoniae, the results of all repeated blood cultures were negative, showing the resolution of sepsis. Van Tuyl et al. [20] also reported a case of a neonate receiving meropenem in meningitic doses of 40 mg/kg/day to treat meropenem-susceptible Enterobacter cloacae in blood culture. The baby developed meropenem-induced neutropenia on the 13th day of therapy, with ANC of 288 cells/mm3. The decision was made to discontinue meropenem on the 19th day of therapy instead of the initially planned 21 days. In the present case, the baby continued to receive meropenem treatment and was managed for hematological problems based on institutional guidelines and culture sensitivity. Initially, hematological changes were not considered as directly meropenem-induced.
Recently published reports also support the notion of carbapenem-induced hematological disorders. A case report by Estella and colleagues [21] described meropenem-induced pancytopenia in a 3-year-old patient at 100 mg/kg given every 8 hours to manage the regrowth of meropenem-sensitive Morganella morganii in CSF cultures. Huang et al. [6] reported a case of meropenem-induced immune thrombocytopenia in a 59-year-old patient, by detecting meropenem-dependent platelet antibodies and platelet count recovery after discontinuation of meropenem. Oka et al. [5] reported the development of severe anemia with clinical signs in a 76-year-old female patient, who received 2 g meropenem per day. On further investigation, they found that a direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG) and C3d, and reported the presence of meropenem-dependent antibodies in the patient’s serum [5].
The absence of drug-dependent antibody testing and bone marrow aspiration prevent us from drawing a firm conclusion regarding the mechanism of meropenem-induced pancytopenia in the present case. However, the hematological findings with the progressive development of thrombocytopenia, anemia, and then neutropenia suggest a possible mechanism of suppression of granulopoiesis or antibody-mediated destruction, as reported in recent studies [5, 6].
During hospitalization, the neonate received other medications, which have been reported to exert hematological effects. The baby initially received ampicillin, gentamicin, and fluconazole, and then received meropenem, colistin, vancomycin, and phenobarbital. However, severe thrombocytopenia developed on the sixth day of the first course of meropenem therapy, when the baby was also on colistin and fluconazole. This issue was resolved when meropenem was discontinued. During the second course of meropenem therapy, the baby again developed severe thrombocytopenia on the third day, while also receiving vancomycin, fluconazole, and phenobarbital. Phenobarbital-induced hematological abnormalities are reported in animal and adult studies [22, 23], and therefore it was discontinued on the sixth day. No seizures were observed but counts did not improve. However, the baby developed severe anemia and neutropenia while receiving fluconazole and meropenem only. After meropenem discontinuation, severe anemia and neutropenia showed a resolving trend for 3 days. Severe neutropenia resolved on the fourth day, and hemoglobin was reported at > 10 g/dl without transfusion on the seventh day of meropenem discontinuation, while fluconazole therapy was continued from the beginning until the 56th DOL, which further confirms the association of meropenem-induced hematological changes in this baby. It was also confirmed that the baby did not experience any additional infection even though she was not discharged on any antibiotic, which correlates with the fast recovery of blood counts after meropenem discontinuation.
Conclusions
In the present neonatal case, the gradual onset of hematological irregularities correlates with the commencement of meropenem therapy, and our observations are also verified by previously published evidence. The follow-up CBC count further established the resolution of pancytopenia after discontinuation of meropenem. Neonatal pancytopenia may lead to serious health complications; therefore, clinicians and pharmacists need to vigilantly monitor CBC counts in this vulnerable population, even when administering meropenem in septic doses for the recommended duration.
Patient perspective
From the perspective of the patient’s father, it was a rare case to have such kind of adverse events in a neonate with the normal treatment regimen. He was shared about all the events and he admired the team for the timely and effectively managing the issues and finally 100% recovery on the follow-ups.
Abbreviations
ANCAbsolute neutrophil count
CBCComplete blood count
DOLDay of life
CPAPContinuous positive airway pressure
TPNTotal parenteral nutrition
SIMVSynchronized intermittent mandatory ventilation
NECNecrotizing enterocolitis
PDAPatent ductus arteriosus
PPHNPersistent pulmonary hypertension of the newborn
CRPC-reactive protein
IDInfectious disease
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We acknowledge the kind support of Abdul Moiz Hussain for providing technical support in the process of final submission and language review. This study was conducted in the neonatal intensive care unit of Aga Khan University Hospital, Karachi, Pakistan.
Authors’ contributions
GA: Substantial contributions to the conception or design of the work. Performed the study, analysis, or interpretation of patient information. Major contributor in writing the manuscript. KH: Supervised the study and analyzed and interpreted the patient data regarding the hematological changes with therapy. Revised the work critically for important intellectual content. SS: Supervised the study and analyzed and interpreted the patient data regarding the hematological changes with therapy. Final approval of the version published. NM: Wrote the initial draft of the case report. AM: Co-wrote the initial draft. SI: data collection and interpretation. JI: data collection and interpretation. All authors read and approved the final manuscript.
Funding
No source of funding in the research.
Availability of data and materials
All data generated or analyzed during this study are included in the published article. The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Please contact the author for data requests.
Ethics approval and consent to participate
This case report was exempted from formal approval by the Ethical Review Committee, Aga Khan University Karachi, Pakistan.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33509295 | 18,915,789 | 2021-01-29 |
What was the outcome of reaction 'Thrombocytopenia neonatal'? | Meropenem-induced pancytopenia in a preterm neonate: a case report.
BACKGROUND
A post-marketing surveillance study has reported an association between meropenem use and the incidence of hematologic abnormalities, including leukopenia, thrombocytopenia, hemolysis, and neutropenia, but the precise incidence in neonates is unknown. Here, we report meropenem-induced pancytopenia in a preterm neonate.
METHODS
A preterm newborn Pakistani received intravenous meropenem 40 mg/kg every 8 hours to treat Klebsiella pneumoniae in blood cultures and suspected meningitis. The baby developed severe thrombocytopenia, with a platelet count of 22 × 103 cells/mm3, low hemoglobin level of 9.7 g/dl, and low absolute neutrophil count (ANC) of 816 cells/mm3 on days 3, 14, and 17 of meropenem therapy, respectively. Based on the blood culture and institutional guidelines, meropenem treatment was continued with monitoring and supportive care for a total of 19 days. After discontinuation of meropenem, the baby was monitored continuously for hematological changes, and low counts persisted for 3 days. ANC improved to > 1500 cells/mm3 on the fourth day, and the platelet count reached > 150 × 103 cells/mm3 for the first time on the seventh day of meropenem discontinuation. All subsequent complete blood count (CBC) reports showed improving trends. The baby was discharged on the 48th day of life (DOL), with follow-up monitoring of CBC. The baby was kept on iron supplements, and hemoglobin level of 11.2 g/dl was observed on the 59th DOL.
CONCLUSIONS
Neonatal pancytopenia may lead to serious health complications; therefore, clinicians and pharmacists need to vigilantly monitor CBC in this vulnerable population, even when administering meropenem in septic doses for the recommended duration.
Background
Pancytopenia is defined as reduced white blood cell (WBC) count, hemoglobin, and platelet count. Pancytopenia occurs when hemoglobin is < 13 g/dl in males and < 12 g/dl in females, absolute neutrophil count (ANC) is < 1500 cells/mm3, and platelet count is < 150 × 103 cells/mm3 [1]. Pancytopenia is considered severe if a patient experiences two or more of the following: hemoglobin < 7 g/dl, ANC < 500 cells/mm3, and platelet count < 50 × 103 cells/mm3. The mechanism underlying pancytopenia mainly involves bone marrow infiltration, bone marrow aplasia, and blood cell destruction that results in peripheral blood leakage [1]. Suppression of bone marrow varies widely in the pediatric population but may occur due to toxins, infection, or malignant cell infiltrates that can lead to hypocellular bone marrow function. Drug-induced pancytopenia is also a rare but secondary cause of bone marrow suppression due to direct bone marrow toxicity, immune-mediated (complement or antibody-mediated) cell destruction, and hapten formation, and directly affects myeloid precursors [2, 3]. An in vitro study of several beta-lactam antibiotics established the presence of well-differentiated myeloid cells and copious granulocyte precursors along with dose-dependent suppression of granulopoiesis [4]. Antibody-mediated hemolytic anemia and thrombocytopenia have also been established in meropenem-treated patients [5, 6]. Several medications can cause pancytopenia including chemotherapeutics, antiepileptics, antidepressants, and antibiotics [3, 5, 7]. A case–control epidemiological surveillance study was conducted over a follow-up period of 78.7 million person-years to assess the incidence of drug-induced agranulocytosis. Around 396 confirmed cases of acute neutropenia were observed, with an overall incidence of 3.5:1 million per year [8]. It was found that agranulocytosis clearly increased the risk of mortality, with a fatality rate of 9.1%. The most common drugs causing agranulocytosis were dipyrone (16%), beta-lactam antibiotics (12.0 %), ticlopidine (11.1%), antithyroid drugs (7.2%), and sulfonamide antibiotics (5.4%) [8].
Meropenem is one of the beta-lactam antibiotics that can cause serious and life-threatening neutropenia. It is a bactericidal broad-spectrum antibiotic with gram-positive, gram-negative, and anaerobic coverage, and is mainly used in the treatment of severe gram-negative infections in neonates including severe sepsis, meningitis, and complicated intra-abdominal infections such as necrotizing enterocolitis (NEC), one of the most common gastrointestinal emergencies and a major cause of morbidity and mortality in preterm neonates. For improved clinical outcomes, early recognition and aggressive management with broad-spectrum or combination antimicrobial agents is most often undertaken to treat NEC [9]. Because of its broad-spectrum activity, meropenem is an agent of great utility [10]. Based on the increasing trends of morbidity and mortality due to multidrug-resistant gram-negative bacterial infections in our neonatal intensive care unit (NICU), and following institutional guidelines, other antibiotics such as vancomycin and colistin are also used [11–13] after infectious disease (ID) consultation. The most common adverse effects of meropenem are constipation or diarrhea, nausea, vomiting, rashes, and diaper-area moniliasis in pediatric patients [14]. Some cases of meropenem-induced neutropenia have been reported [15]. However, no known case of meropenem-induced pancytopenia in neonates has yet been published. Here we report an event of meropenem-induced pancytopenia in a neonate admitted to the NICU of a tertiary-care hospital.
Case presentation
A newborn Pakistani baby was transferred to the intensive care unit due to prematurity, low birth weight, and intrauterine growth retardation. Her birth weight was 0.71 kg and APGAR scores were 3 at 1 minute and 4 at 5 minutes. Delivered by emergency C-section at 29 weeks due to raised blood pressure and fetal distress, she was initially kept on continuous positive airway pressure (CPAP) and given nothing through the mouth, and total parenteral nutrition (TPN) was started. Caffeine was loaded at 20 mg/kg and continued as the standard of care for apnea of prematurity. A prophylactic dose of 1 mg of vitamin K was given. During the first 24 hours, complete blood count (CBC) results were WBC of 18.3 × 103 cells/mm3, ANC of 1244 cells/mm3, platelet count of 166 × 103 cells/mm3, and hemoglobin of 17.8 g/dl. On the second day of life (DOL), ampicillin and gentamicin were started as empirical therapy, and the CBC report showed WBC 4 × 103 cells/mm3, ANC of 760 cells/mm3, platelet count of 152 × 103 cells/mm3, and hemoglobin of 15.9 g/dl. In addition, fluconazole was started as antifungal prophylaxis. The patient was given phototherapy. Chest X-ray and ultrasound of the head were performed, with normal findings. CPAP was tapered to high flow on merit, and blood culture was sent.
On the fourth DOL, the baby developed issues of severe respiratory distress and abdominal distension along with metabolic acidosis. She was intubated and kept on synchronized intermittent mandatory ventilation (SIMV) mode. The CBC results showed ANC of 912 cells/mm3, platelet count of 99 × 103 cells/mm3, and hemoglobin of 12.7 g/dl. Inotropic support was started, and antibiotics were escalated to meropenem 20 mg/kg every 12 hours, vancomycin 10 mg/kg once daily, and colistin at a loading dose of 5 mg/kg with a maintenance dose of 1.5 mg/kg every 12 hours. Blood culture showed no growth. After ID consult, vancomycin was discontinued on the third day and a decision was made to continue meropenem and colistin [11–13] to manage NEC and sepsis.
On the fifth DOL, echocardiogram was performed and showed patent ductus arteriosus (PDA) of 3 mm with severe persistent pulmonary hypertension of the newborn (PPHN). Acetaminophen was started for the next 5 days. On the sixth day of meropenem therapy, the platelet count dropped to 42 × 103 cells/mm3, treated in line with sepsis-associated thrombocytopenia [16], and managed by transfusion of 10 ml/kg platelet units [17]. Meropenem and colistin were discontinued on the eighth day of therapy, and trophic feeding was started. An echocardiogram was repeated on day 11, which showed a closed PDA and moderate PPHN. On the 18th DOL, the child was successfully extubated and kept on high-flow oxygen. There was slow progress in feeding.
On the 22nd DOL, the baby had tachycardia and an episode of 99.7 °F fever. Thus, septic workup was done and showed WBC count of 17.4 × 103 cells/mm3, ANC of 12,632.4 cells/mm3, and platelets of 203 × 103 cells/mm3. C-reactive protein (CRP) was 77 mg/l and renal function was normal (blood urea nitrogen [BUN] of 11 mg/dl and creatinine of 0.2 mg/dl). Meropenem was started in meningitic doses of 40 mg/kg every 8 hours [10] along with vancomycin 15 mg/kg every 12 hours.
In the microbiological investigation, urine and cerebrospinal fluid (CSF) cultures were found to be negative, but the blood culture was positive for Staphylococcus species (not aureus). Blood culture repeated after 48 hours was positive for carbapenem-sensitive Klebsiella pneumoniae. The baby was moved to the isolation room. On the 24th DOL, the baby developed severe thrombocytopenia, with a platelet count of 22 × 103 cells/mm3, managed with the transfusion of 10 ml/kg platelet units [17].
On the 25th DOL, an episode of generalized tonic-clonic fit occurred for which single-dose diazepam and a loading dose of phenobarbitone were given initially and then continued with maintenance doses of phenobarbitone. Due to significant metabolic acidosis and desaturation, the baby was re-intubated. After ID consult, meropenem was continued in meningitic doses and vancomycin was discontinued. SIMV and a central line were placed. TPN was started with nothing per oral status.
Blood gases were monitored, and the baby was extubated after 4 days and switched to CPAP. Phenobarbitone was discontinued after 6 days of therapy, and the baby was seizure-free through the remainder of the hospital stay. All repeat blood cultures were negative for any growth including CSF culture. The ID team was on board and decided to continue meropenem for a total of 14 days post-negative culture in septic doses of 20 mg/kg, and vancomycin was discontinued after 6 days. All repeated blood cultures obtained on the 27th and 30th DOL confirmed no pathogenic growth.
On the 33rd DOL, the CBC report showed WBC of 8.7 × 103 cells/mm3, ANC of 4576 cells/mm3, platelets of 78 × 103 cells/mm3, and hemoglobin of 10.8 g/dl. On the 36th DOL, the CBC report showed WBC of 5.1 × 103 cells/mm3, ANC of 2917 cells/mm3, platelets of 29 × 103 cells/mm3, and hemoglobin of 9.2 g/dl. The baby was managed for thrombocytopenia with platelet transfusion.
On the 37th DOL, hemoglobin dropped to 8.3 g/dl in the evening, and platelet count improved to 63 × 103 cells/mm3, WBC was 4.8 × 103 cells/mm3, and ANC was 1285 cells/mm3. On the 39th DOL, a marked reduction was observed in ANC to 816 cells/mm3, platelets of 38 × 103 cells/mm3, and hemoglobin of 8.3 g/dl, and the baby received blood transfusion to manage it. For constant issues, a hematological consult was taken and a decision was made to manage the baby symptomatically with 10 ml/kg platelet units at a platelet count < 50 [17] and 15 ml/kg packed cell transfusion at hemoglobin < 10 g/dl [18].
On the 40th DOL, meropenem was discontinued 14 days after negative culture (total of 19 days of meropenem therapy). On the same day the platelet count was 34 × 103 cells/mm3, ANC was 818 cells/mm3, and hemoglobin was 10.2 g/dl, and the baby was transfused to manage these issues. After discontinuation of meropenem, the baby was continuously monitored for hematological changes, and low counts persisted for 3 days. Improved ANC of > 1500 cells/mm3 was reported on the fourth day, and platelet count of > 150 × 103 cells/mm3 was reported for the first time on the sixth day of meropenem discontinuation, but hemoglobin was still low (Fig 1). CPAP was tapered gradually to nasal prongs. The peripherally inserted central catheter was removed, and orogastric (OG) tube feeding was commenced. The baby was discharged on the 48th DOL on iron supplements with follow-up monitoring of CBC. Hemoglobin level of 11.2 g/dl was found on the 59th DOL.Fig. 1. Hematological changes and timing of medication during hospitalization
Discussion
Drug-induced pancytopenia is a rare hematological problem in neonatal clinical practices, evaluated based on a complete underlying pathological history, physical examination, and vigilant interpretation of biochemical, radiological, histopathological, and hematological findings [19]. Concerns have been raised about hematological adverse effects of several beta-lactamase inhibitors [8]. This neonatal case documents meropenem-induced pancytopenia and emphasizes cautious laboratory monitoring for patients receiving meropenem therapy.
Sepsis is another known etiology of pancytopenia. Although the neonate in the present case had a blood culture positive for K. pneumoniae, the results of all repeated blood cultures were negative, showing the resolution of sepsis. Van Tuyl et al. [20] also reported a case of a neonate receiving meropenem in meningitic doses of 40 mg/kg/day to treat meropenem-susceptible Enterobacter cloacae in blood culture. The baby developed meropenem-induced neutropenia on the 13th day of therapy, with ANC of 288 cells/mm3. The decision was made to discontinue meropenem on the 19th day of therapy instead of the initially planned 21 days. In the present case, the baby continued to receive meropenem treatment and was managed for hematological problems based on institutional guidelines and culture sensitivity. Initially, hematological changes were not considered as directly meropenem-induced.
Recently published reports also support the notion of carbapenem-induced hematological disorders. A case report by Estella and colleagues [21] described meropenem-induced pancytopenia in a 3-year-old patient at 100 mg/kg given every 8 hours to manage the regrowth of meropenem-sensitive Morganella morganii in CSF cultures. Huang et al. [6] reported a case of meropenem-induced immune thrombocytopenia in a 59-year-old patient, by detecting meropenem-dependent platelet antibodies and platelet count recovery after discontinuation of meropenem. Oka et al. [5] reported the development of severe anemia with clinical signs in a 76-year-old female patient, who received 2 g meropenem per day. On further investigation, they found that a direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG) and C3d, and reported the presence of meropenem-dependent antibodies in the patient’s serum [5].
The absence of drug-dependent antibody testing and bone marrow aspiration prevent us from drawing a firm conclusion regarding the mechanism of meropenem-induced pancytopenia in the present case. However, the hematological findings with the progressive development of thrombocytopenia, anemia, and then neutropenia suggest a possible mechanism of suppression of granulopoiesis or antibody-mediated destruction, as reported in recent studies [5, 6].
During hospitalization, the neonate received other medications, which have been reported to exert hematological effects. The baby initially received ampicillin, gentamicin, and fluconazole, and then received meropenem, colistin, vancomycin, and phenobarbital. However, severe thrombocytopenia developed on the sixth day of the first course of meropenem therapy, when the baby was also on colistin and fluconazole. This issue was resolved when meropenem was discontinued. During the second course of meropenem therapy, the baby again developed severe thrombocytopenia on the third day, while also receiving vancomycin, fluconazole, and phenobarbital. Phenobarbital-induced hematological abnormalities are reported in animal and adult studies [22, 23], and therefore it was discontinued on the sixth day. No seizures were observed but counts did not improve. However, the baby developed severe anemia and neutropenia while receiving fluconazole and meropenem only. After meropenem discontinuation, severe anemia and neutropenia showed a resolving trend for 3 days. Severe neutropenia resolved on the fourth day, and hemoglobin was reported at > 10 g/dl without transfusion on the seventh day of meropenem discontinuation, while fluconazole therapy was continued from the beginning until the 56th DOL, which further confirms the association of meropenem-induced hematological changes in this baby. It was also confirmed that the baby did not experience any additional infection even though she was not discharged on any antibiotic, which correlates with the fast recovery of blood counts after meropenem discontinuation.
Conclusions
In the present neonatal case, the gradual onset of hematological irregularities correlates with the commencement of meropenem therapy, and our observations are also verified by previously published evidence. The follow-up CBC count further established the resolution of pancytopenia after discontinuation of meropenem. Neonatal pancytopenia may lead to serious health complications; therefore, clinicians and pharmacists need to vigilantly monitor CBC counts in this vulnerable population, even when administering meropenem in septic doses for the recommended duration.
Patient perspective
From the perspective of the patient’s father, it was a rare case to have such kind of adverse events in a neonate with the normal treatment regimen. He was shared about all the events and he admired the team for the timely and effectively managing the issues and finally 100% recovery on the follow-ups.
Abbreviations
ANCAbsolute neutrophil count
CBCComplete blood count
DOLDay of life
CPAPContinuous positive airway pressure
TPNTotal parenteral nutrition
SIMVSynchronized intermittent mandatory ventilation
NECNecrotizing enterocolitis
PDAPatent ductus arteriosus
PPHNPersistent pulmonary hypertension of the newborn
CRPC-reactive protein
IDInfectious disease
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We acknowledge the kind support of Abdul Moiz Hussain for providing technical support in the process of final submission and language review. This study was conducted in the neonatal intensive care unit of Aga Khan University Hospital, Karachi, Pakistan.
Authors’ contributions
GA: Substantial contributions to the conception or design of the work. Performed the study, analysis, or interpretation of patient information. Major contributor in writing the manuscript. KH: Supervised the study and analyzed and interpreted the patient data regarding the hematological changes with therapy. Revised the work critically for important intellectual content. SS: Supervised the study and analyzed and interpreted the patient data regarding the hematological changes with therapy. Final approval of the version published. NM: Wrote the initial draft of the case report. AM: Co-wrote the initial draft. SI: data collection and interpretation. JI: data collection and interpretation. All authors read and approved the final manuscript.
Funding
No source of funding in the research.
Availability of data and materials
All data generated or analyzed during this study are included in the published article. The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Please contact the author for data requests.
Ethics approval and consent to participate
This case report was exempted from formal approval by the Ethical Review Committee, Aga Khan University Karachi, Pakistan.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33509295 | 18,915,789 | 2021-01-29 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile neutropenia'. | Clinical pattern of failure after a durable response to immune check inhibitors in non-small cell lung cancer patients.
Although immune checkpoint inhibitors (ICIs) can induce durable responses in non-small-cell lung cancer (NSCLC) patients, a significant proportion of responders still experience progressive disease after a period of response. Limited data are available on the clinical patterns of acquired resistance (AR) to ICIs. Clinical and radiologic data from 125 NSCLC patients treated with anti-PD-1 or PD-L1 antibodies between 2011 and 2018 at two tertiary academic institutions were retrospectively reviewed. Overall, 63 (50.4%) patients experienced AR after ICI treatment in a median of 10.7 months. Among the 13 patients with a partial response with ICI, 12 (32.4%) had only lymph node progression. Most patients (n = 52, 82.5%) had one or two sites with progression (oligo-progression). The median overall survival (OS) after progression was significantly longer in the extrathoracic group than in the thoracic and liver progression groups (30.2 months [95% confidence interval (CI), 13.4 to not reached (NR)], 11.7 months [95% CI, 9.5-21.1], and 5.4 months [95% CI, 2.6-NR], respectively, P < 0.001). Patients with oligo-progression had significantly longer OS after AR than did the multi-progression patients (18.9 months [95% CI, 10.6-NR] vs. 8.8 months [95% CI, 5.7-NR], P = 0.04). No significant difference in progression-free survival was observed between the subsequent chemotherapy and the ICI after AR groups (P = 0.723). Patients with AR after ICI treatment had a unique progression pattern with oligo-progression and high rates of progression only in the lymph nodes. Local treatment and/or continuation of ICIs beyond AR might be an effective option.
Introduction
Immune checkpoint inhibitors (ICIs), including anti- programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) antibodies, represent a breakthrough in the treatment of non-small-cell lung cancer (NSCLC). Previous studies have shown that high levels of PD-L1 expression on tumors and/or immune cells by immunohistochemistry are associated with improved clinical efficacy when compared with low levels or negative PD-L11–6. In patients with pretreated advanced NSCLC, ICI monotherapy resulted in durable clinical responses lasting more than 6 months and enabled patients to achieve 5-year overall survival (OS) without subsequent therapy and disease progression6–8. However, a significant proportion of long-term responders still experience progressive disease after a period of response time.
Acquired resistance (AR) refers to a clinical scenario in which cancer initially responds to immunotherapy, but it continues to grow and metastasize to other organs after a period of time. In the epidermal growth factor receptor (EGFR) mutant NSCLC, it is well-known that acquired mutations, including T790M, confer AR to tumors after EGFR tyrosine kinase inhibitor (TKI) treatment9. However, among patients with ICI treatment, more efforts are needed to elucidate which patients will experience AR and how tumor evolution or changes in the immune system lead to AR development. Defects in interferon-receptor signaling and antigen presentation pathways, tumor-associated neoantigen loss, alternate immune checkpoints, and alterations in the tumor microenvironment are believed to be involved in AR mechanisms10–12.
Recently, Gettinger et al.13 presented an impressive single-institution case series of 26 NSCLC patients who experienced AR of the PD-1 blockade. The authors reported the lymph node (LN) as the most common site of AR; their study included 11 cases with only LN progression. The majority of the included patients (88%) showed progression in one or two sites of disease. Overall, 15 (58%) patients received local therapy to sites of AR, while 11 (42%) patients continued immunotherapy beyond progression14. To date, clinical data regarding subsequent treatment strategies and survival according to progression patterns after AR to ICI in NSCLC patients is sparse, especially for those with durable responses.
Therefore, in this study, we conducted a retrospective analysis to investigate the clinical patterns of AR after a durable response to ICIs in NSCLC patients. Additionally, we determined the implications for subsequent therapy in these patients.
Results
Patient characteristics
Of the 125 patients with a durable clinical benefit more than 6 months, 63 (50.4%) patients with AR to ICIs were identified. The baseline clinicopathological characteristics of these patients are summarized in Table 1. The majority (n = 47, 74.6%) of the patients were male, and just over half of the patients were pathologically diagnosed with adenocarcinoma (n = 35, 55.5%). The majority of patients received ICI as first or second-line treatment for metastatic NSCLC (n = 47, 74.6%); 21 (33.3%) and 26 (41.3%) patients received it as first and second-line treatment, respectively. The study included 15 (23.8%) patients with driver mutations. Fifty-two (82.5%) patients received monotherapy, while 11 (17.5%) patients received combination therapy, including five (7.9%) patients with PD-1 and CTLA-4 inhibitors, five (7.9%) patients with PD-L1 and CTLA-4 inhibitors, and one (1.6%) patient with a PD-1 inhibitor and chemotherapy. The median duration of follow-up was 18 months (range, 8–60) and 23 (36.5%) patients were alive at the time of data analysis in December 2018.Table 1 Patient characteristics.
N = 63
Age (years)
Median (range) 64 (34–84)
Sex
Male 47 (74.6)
Female 16 (25.4)
Ethnicity
Asian 63 (100.0)
Smoking
Never smoked 21 (33.3)
Current or ex-smoker 42 (66.7)
Pathology
Adenocarcinoma 35 (55.5)
Poorly differentiated 4 (6.3)
Sarcomatoid 3 (4.8)
Large cell neuroendocrine 2 (3.2)
Squamous 19 (30.2)
Driver mutation
EGFR 11 (17.4)
KRAS 2 (3.2)
ALK 1 (1.6)
ROS1 1 (1.6)
Not identified 48 (76.2)
ICI treatment line
1 21 (33.3)
2 26 (41.3)
≥ 3 16 (25.4)
ICI treatment
PD-1 inhibitor 36 (57.1)
PD-L1 inhibitor 16 (25.4)
PD-1 inhibitor + CTLA-4 inhibitor 5 (7.9)
PD-L1 inhibitor + CTLA-4 inhibitor 5 (7.9)
PD-1 inhibitor + chemotherapy 1 (1.6)
PD-L1 expression
≥ 50% 18 (28.6)
1–49% 10 (15.9)
0% 11 (17.5)
Not available 24 (38.1)
Best objective response
Stable disease 26 (41.3)
Partial response 37 (58.7)
Complete response 0 (0)
EGFR epidermal growth factor receptor, ALK anaplastic lymphoma kinase, PD-1 programmed death 1, PD-L1 programmed death ligand 1, CTLA-4 Cytotoxic T-Lymphocyte Associated Protein 4.
*Data are presented as the median (range) or number (%).
Clinical patterns of ICI failure
Among all the included patients, the median time to AR was 10.7 months. The clinical patterns of AR after ICI treatment are summarized in Table 2 and shown based on their best objective response in Fig. 1.
The most common site of progressive disease was the lungs (38/63, 60.3%), followed by the LNs (31/63, 49.2%), and the brain (6/63, 9.5%). One of fifth (14/63, 22.2%) of patients had only LN progression at the time of AR. Twelve (85.7%) of the 14 patients with LN progression only had achieved PR as their best response, while 2 (14.3%) of the 14 patients achieved SD during ICI treatment (P = 0.04).Table 2 Clinical Patterns of the failure of immune checkpoint inhibitors.
All patients 1st/2nd line ICI ≥ 3rd line ICI P-value
(n = 63) (n = 47) (n = 16)
Previous best response
PR 37 (58.7) 16 (34.0) 6 (37.5) 0.089
SD (≥ 6 months) 26 (41.3) 31 (66.0) 10 (62.5)
Time to acquired resistance
Median (range) 10.7 (6.0–47.2) 10.8 (6.0–47.2) 10.2 (6.4–22.9) 0.052
Overall survival after progression
Median (range) 10.9 (0.0–43.7) 11.5 (0.0–43.7) 9.6 (0.0–30.4) 0.775
Number of progression sites
1 46 (73.0) 36 (76.6) 10 (62.5) 0.553
2 6 (9.5) 4 (8.5) 2 (12.5)
≥ 3 11 (17.5) 7 (14.9) 4 (25.0)
Progression sitea
Lung 38 (60.3) 23 (48.9) 15 (93.8) 0.004
Non-lung visceral organ
Liver 4 (6.3) 2 (4.3) 2 (12.5) 1
Colon 1 (1.6) 1 (2.1) 0 (0)
Adrenal gland 1 (1.6) 1 (2.1) 0 (0)
Heart (pericardium) 2 (3.2) 1 (2.1) 1 (6.2)
Brain 6 (9.5) 5 (10.6) 1 (6.2)
Bone 4 (6.3) 2 (4.3) 2 (12.5) 1
Lymph node 31 24 7 0.265
Neck 5 (7.9) 3 (6.4) 2 (12.5) 0.274
Axilla 2 (3.2) 1 (2.1) 1 (6.2)
Thoracic 20 (32.7) 16 (34.0) 4 (25.0)
Abdomen 4 (6.3) 4 (6.3) 0 (0)
Pre-existence of progression site
New only 13 (20.6) 11 (23.4) 1 (6.2) 0.201
Existing only 43 (68.3) 32 (68.1) 12 (75.0)
Both new and existing 7 (11.1) 4 (8.5) 3 (18.8)
Pattern of progression sites
Lymph node only 14 (22.2) 14 (30.0)) 0 (0) 0.013
Extranodal organs 49 (77.8) 33 (70.0) 16 (100)
Bold values denote statistical significance at the p < 0.05 level
ICI immune checkpoint inhibitors, PR partial response, SD stable disease.
aPatients were included in more than one group based on the site of progression.
Figure 1 Donut plot showing sites of acquired resistance by best objective response to immune checkpoint inhibitors. LN lymph node, PR partial response, SD stable disease.
Next, we evaluated the pattern of failure according to the type of ICI treatment. Less frequent lung progression was observed in patients treated with ICI as first- or second-line treatment than in patients treated with ICI as at least third-line treatment (48.9% vs. 93.8%; P value = 0.039). Progressive disease only in the LNs was observed among the patients who received first- or second line-treatment. There were no statistically significant differences between the two groups regarding the number of progression sites, previous best response, and the pre-existence of progression sites.
The clinical patterns of AR based on the number of progression sites are summarized in Table 3. Fifty-two (82.5%) patients had progression in one or two lesions (oligo-progression group), while 11 (25.4%) patients had progression in three or more lesions (multi-progression group). The lungs were the most frequent sites of progression in both groups. Progression of new lesions only was observed among 12 (23.1%) and 0 (0%) patients with oligo-progression and multi-progression, respectively (P < 0.001). Progression in the LNs only was also more frequent in patients with oligo-progression compared to patients with multi-progression (27.0% vs. 0%, P = 0.103).Table 3 Baseline characteristics based on oligo-progression.
Oligo-progression Multiple progression P-value
(Progression site 1–2) (Progression site 3 ≤)
(n = 52) (n = 11)
Age (years)
Median (range) 64 (34–84) 62 (49–74) 0.752
Sex
Male 38 (73.1) 9 (81.8) 0.714
Female 14 (26.9) 2 (18.2)
Smoking
Never smoked 19 (36.5) 2 (18.2) 0.31
Current or ex-smoker 33 (63.5) 9 (81.8)
Pathology
Squamous 16 (30.8) 3 (27.3) 0.822
Non-Squamous 36 (69.2) 8 (62.7)
ICI treatment line
01-Feb 40 (76.9) 7 (63.6) 0.449
3 ≤ 12 (23.1) 4 (36.4)
Monotherapy
PD-1 inhibitor 27 (51.9) 9 (81.8)
PD-L1 inhibitor 16 (30.8) 0 (0)
Combination therapy
PD-1 inhibitor + chemotherapy 1 (1.9) 0 (0)
PD-1 inhibitor + CTLA-4 inhibitor 3 (5.8) 2 (18.2)
PD-L1 inhibitor + CTLA-4 inhibitor 5 (9.6) 0 (0.0)
Previous response
SD 29 (55.8) 8 (72.7) 0.502
PR 23 (44.2) 3 (27.3)
Progression sitea
Lung 28 (53.8) 10 (90.9) 0.039
Non-lung visceral organ
Liver 2 (3.8) 2 (18.2) 0.275
Colon 1 (1.9) 0 (0)
Adrenal gland 1 (1.9) 0 (0)
Heart (pericardium) 1 (1.9) 1 (9.1)
Brain 5 (9.6) 1 (9.1) 1
Bone 1 (1.9) 3 (27.3) 0.015
Lymph node 14 (23.6) 11 (100) < 0.001
Neck 3 (5.8) 1 (9.1)
Axilla 1 (1.9) 1 (9.1)
Thoracic 10 (15.9) 10 (90.9)
Abdomen 4 (6.3) 0 (0)
Pre-existence of progression site
New only 12 (23.1) 0 (0) < 0.001
Existing only 39 (75.0) 5 (45.5)
Both new and existing 1 (1.9) 6 (54.5)
Pattern of progression sites
Lymph node only 14 (27.0) 0 (0) 0.103
Extranodal organs 38 (73.0) 11 (100.0)
Bold values denote statistical significance at the p < 0.05 level
PR partial response, SD stable disease, PD-1 programmed death 1, PD-L1 programmed death ligand 1, CTLA-4 Cytotoxic T-Lymphocyte Associated Protein 4.
aPatients can be included in more than one group based on the site of progression13.
Survival differences based on the progression patterns
The median OS after AR was 10.9 months. OS after AR was analyzed according to the pattern of progression. When the patients were classified into subgroups (i.e. those who had intrathoracic, extrathoracic [excluding the liver], and liver progression), the median OS after progression was significantly longer in the extrathoracic subgroup than in the thoracic and liver progression subgroups (30.2 months [95% CI, 13.4 to not reached (NR)], 11.7 months [95% CI, 9.5–21.1], and 5.4 months [95% CI, 2.6-NR], respectively, P < 0.001, Fig. 2A). The median OS after progression was significantly longer in the oligo-progression group compared to that in the multiple progression group (18.9 months [95% CI, 10.6-NR] vs. 8.8 months [95% CI, 5.7-NR], P = 0.04, Fig. 2B). The progression patterns were not statistically significant when classified by progression in new lesions (Fig. 2C) nor nodal progression (Fig. 2D).Figure 2 Kaplan–Meier survival curves showing overall survival from the point of acquired resistance for (A) the subgroup that had thoracic, extrathoracic, and liver progression only (B) the subgroup that had one or two progression sites or more than three progression sites (C) the subgroup that had progression from new lesions, existing lesions, and both new and existing lesions (D) the subgroup that had only lymph node and extranodal progression (including the lung).
Subsequent therapy after AR
Among the 63 patients with AR to ICIs, 52 (82.5%) patients received subsequent therapy after progression. Eleven (21.2%) patients received local treatment, including radiotherapy and surgical resection. Forty-one (78.8%) patients underwent systemic therapy after progression, including 25 (48.1%) and 16 (30.8%) patients who received cytotoxic chemotherapy and ICI after progression (Table 4). The median OS of the local therapy, chemotherapy, and ICI groups was 27.4, 23.2, and 29.1 months, respectively; there was no significant difference in survival between these groups (P = 0.787, Fig. 3A). Additionally, there was no significant difference in the PFS between the chemotherapy and the ICI groups (P = 0.723, Fig. 3B).Table 4 Subsequent therapy after progression.
All patients
(n = 52) 1st/2nd line ICI
(n = 40) ≥ 3rd line ICI
(n = 12)
Local therapy (n = 11)
Surgery 2 (3.8) 2 (5.0) 0 (0)
Radiotherapy 7 (13.5) 6 (15.0) 1 (8.3)
Gamma-knife surgery 2 (3.8) 2 (5.0)) 0 (0)
Systemic therapy (n = 41)
Immunotherapy 16 (30.8) 16 (40.0) 0 (0.0)
Chemotherapy 25 (48.1) 16 (40.0) 9 (75.0)
All patients
(n = 52) Oligo-progression
(Progression site 1–2)
(n = 43) Multiple progression
(Progression site 3 ≤)
(n = 9)
Local therapy (n = 11)
Surgery 2 (3.8) 2 (4.7) 0 (0)
Radiotherapy 7 (13.5) 6 (14.0) 1 (11.1)
Gamma-knife surgery 2 (3.8) 2 (4.7) 0 (0)
Systemic therapy (n = 41)
Immunotherapy 16 (30.8) 14 (32.6) 2 (22.2)
chemotherapy 25 (48.1) 19 (44.2) 6 (66.7)
Local therapy (n = 11) Surgery Colon mass excision (1)
Axilla LN excision (1)
Radiotherapy Abdomen LN (2)
Neck & SCN LN (1)
Lung mass (2)
Bone (2)
Gamma-knife surgery Brain (2)
ICI immune checkpoint inhibitors.
Figure 3 Kaplan–Meier survival curves showing (A) overall survival from the point of acquired resistance based on the subgroups of subsequent treatment (B) progression free survival based on the subsequent treatment.
Discussion
In this study, after a median time of 10.4 months, patients who had a durable clinical benefit experienced AR. The majority of these patients (52/63, 82.5%) had progressive disease in one or two sites. Progression in the LNs only was observed in 22.2% patients at the time of AR; such patients received ICI as first or second-line treatment. Most (12/14, 85.7%) patients with progression in the LNs only had objective tumor shrinkage, partial response according to RECIST, during ICI treatment. Among patients with oligo-progression (n = 52), progression of the LNs only (27.0%) or appearance of new lesions without evident progression of pre-existing lesions (23.1%) was observed. The patterns of progression observed in this cohort of patients with NSCLC at the time of AR are very unique considering that most patients treated in the conventional chemotherapy era develop systemic progression including pre-existing diseases. Even after having AR, patients with oligo-progression could be treated with local ablative therapy or continued ICI beyond AR. In the survival analysis, there was significantly longer OS among the oligo-progressors compared to that among systemic or multiple site progressors. We observed no significant difference in terms of PFS and OS between patients with subsequent chemotherapy and those with continuation of ICI beyond progression.
A notable finding in our study was that a significant portion of patients with AR to ICIs had progression of the LNs only, with sustained anti-cancer efficacy of ICI in pre-existing lesions. Among patients with a PR response with ICI (n = 37, 58.7%), 12 (32.4%) patients had progression of the LNs only. In the previous study by Gettinger et al. it was also reported that 42% of NSCLC patients who achieved PR after ICI treatment had AR limited to the LNs11. The study also suggested that the malignant LN environment may lead to the immunosuppressive evolution of cells within the node.
It should be also noted that that patients with oligo-progression showed prolonged OS compared to those with multi-progression after AR in our study. Potential hypotheses for this finding might be the “the cancer-immunity cycle”15. Tumors in still “immune surveillance active” hosts are not able to proliferate or metastasize to other organs unless they obtain the novel phenotype of immune evasion. Therefore, it is easily conceivable that lung cancer clones in the progressive site might have evolved to escape host immune surveillance with either loss of heterozygosity in human leukocyte antigens or depletion of the expressed neoantigens16.
In this study, physicians preferred local therapy and immunotherapy beyond progression for patients with oligo-progression. For NSCLC, there was an interesting retrospective report from the phase III OAK study that atezolizumab showed acceptable efficacy and safety after progression with patients with good performance17. To date, ICI has been reported to show post-progression efficacies in a limited subset of patients including those with metastatic urothelial carcinoma, renal cell carcinoma and melanoma, and NSCLC18–22. However, whether treatment beyond progression will be effective is not yet elucidated in patients with AR. Gettinger et al. reported that 11 NSCLC patients continued immunotherapy beyond AR13. Adam LC et al. reported an AR case of successful local control with cryotherapy combined with immunotherapy beyond progression23. Further analysis will help to define the clinical benefit for NSCLC patients with a durable response treated with ICI beyond progression.
There are several limitations to this study. First, this was a retrospective analysis. As not many patients showed a durable response to ICI, only a small number of patients were included in the study, resulting in limited statistical power. Therefore, the small study size prohibited us from performing comparisons between the different subgroups. Second, the study population was very diverse, including not only patients with PD-1 inhibitor or PD-L1 inhibitor monotherapy, but also patients with combination therapy including cytotoxic drugs or CTLA-4 inhibitors. Third, although the PD-L1 expression profile is a very important prognostic factor, our study included the PD-L1 profile utilizing three different anti-PD-L1 antibodies (22C3, E1L3N, and SP263). As most of the patients (81.0%) were involved in clinical trials, we were not able to ascertain the immunohistochemistry profiles for some patients, due to patient information protection regulations. Besides, information on co-medication such as antibiotics, corticosteroids, opioids, or proton pump inhibitors, which can affect ICI response, was not fully available. Lastly, there may be bias in the selection of subsequent therapy, as each individual physician was responsible for selecting the appropriate treatment.
Despite these limitations, our study described the clinical features and patterns of AR in detail. To our knowledge, this is the first study to show survival differences based on progression patterns. We believe that this report may provide useful information to clinicians regarding advanced NSCLC patients; additionally, it highlights the implications of subsequent therapy after AR.
In conclusion, advanced NSCLC patients who had durable responses (> 6 months) showed unique patterns of progression with high rates of progression among the LN only, in addition to oligo-progression. Local treatment and/or continuation of ICIs beyond AR might be an effective option for those patients. Further large-scale prospective studies are required to confirm these findings.
Methods
Design, patients, and data collection
We retrospectively reviewed the records of patients diagnosed with NSCLC and treated with inhibitors of PD-1 and PD-L1 at the Seoul National University Hospital (SNUH) and Seoul National University Bundang Hospital (SNUBH) between January 1, 2011 and November 31, 2018.
Adults without a previous history of severe systemic disease or autoimmune diseases who received PD-1/PD-L1 blockade alone or with cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor or chemotherapy over the course of disease were included.
Patient classification and outcome measures
The patients were classified into the following subgroups: those who had intrathoracic, extrathoracic [excluding the liver], and liver progression. AR after durable response was defined as disease progression after 6 months with the best response of the stable disease, partial response, or complete response according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criterion. Imaging studies included Computed tomography scan and Magnetic resonance imaging and were independently reviewed by two observers. Progression-free survival (PFS) was calculated from the ICI treatment initiation date to the date of disease progression using the RECIST v1.1 criteria24, as confirmed by imaging, death, or the last follow-up date, if censored. OS was measured from the initiation of ICI treatment until death or the last follow-up date, if censored.
Statistical analyses
Continuous variables were compared using the Students t-test or the Mann–Whitney U-test, whereas categorical variables were compared using the chi-squared or Fisher exact tests. Survival analyses were conducted according to the Kaplan–Meier method using the log-rank test. All tests were two-sided and p-values < 0.05 were considered to be statistically significant. For survival analysis, R version 3.4.3 software (R Development Core Team, https://www.r-project.org/) was used for computation.
Ethics
All the included patients provided written, informed consent for data collection before treatment. The research team conducted retrospective analyses on cohort data. The institutional review boards of SNUH and SNUBH approved the study protocol (IRB number: B-2004-606-105). All procedures were carried out in accordance with the ethical standards of the institutional research ethics committee and the Helsinki declaration revised in 2013 by the World Medical Association.
Supplementary Information
Supplementary Table 1.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material availlable at 10.1038/s41598-021-81666-x.
Acknowledgements
This study was supported by the Grants from the SNUBH Research Fund (Grant Number: 13-2017-002 to SH Kim).
Author contributions
Writing: J.Y.H. Data acquisition: J.Y.H and S.H.Y, Supervision and review: C.O, M.K., B.K., T.M.K., D.K., D.S.H , K.J.S., S.H.K., Y.J.K. and J.S.L. Editing: J.Y.H. and S.H.K.
Competing interests
The authors declare no competing interests. | NIVOLUMAB | DrugsGivenReaction | CC BY | 33510255 | 18,971,720 | 2021-01-28 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonitis'. | Clinical pattern of failure after a durable response to immune check inhibitors in non-small cell lung cancer patients.
Although immune checkpoint inhibitors (ICIs) can induce durable responses in non-small-cell lung cancer (NSCLC) patients, a significant proportion of responders still experience progressive disease after a period of response. Limited data are available on the clinical patterns of acquired resistance (AR) to ICIs. Clinical and radiologic data from 125 NSCLC patients treated with anti-PD-1 or PD-L1 antibodies between 2011 and 2018 at two tertiary academic institutions were retrospectively reviewed. Overall, 63 (50.4%) patients experienced AR after ICI treatment in a median of 10.7 months. Among the 13 patients with a partial response with ICI, 12 (32.4%) had only lymph node progression. Most patients (n = 52, 82.5%) had one or two sites with progression (oligo-progression). The median overall survival (OS) after progression was significantly longer in the extrathoracic group than in the thoracic and liver progression groups (30.2 months [95% confidence interval (CI), 13.4 to not reached (NR)], 11.7 months [95% CI, 9.5-21.1], and 5.4 months [95% CI, 2.6-NR], respectively, P < 0.001). Patients with oligo-progression had significantly longer OS after AR than did the multi-progression patients (18.9 months [95% CI, 10.6-NR] vs. 8.8 months [95% CI, 5.7-NR], P = 0.04). No significant difference in progression-free survival was observed between the subsequent chemotherapy and the ICI after AR groups (P = 0.723). Patients with AR after ICI treatment had a unique progression pattern with oligo-progression and high rates of progression only in the lymph nodes. Local treatment and/or continuation of ICIs beyond AR might be an effective option.
Introduction
Immune checkpoint inhibitors (ICIs), including anti- programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) antibodies, represent a breakthrough in the treatment of non-small-cell lung cancer (NSCLC). Previous studies have shown that high levels of PD-L1 expression on tumors and/or immune cells by immunohistochemistry are associated with improved clinical efficacy when compared with low levels or negative PD-L11–6. In patients with pretreated advanced NSCLC, ICI monotherapy resulted in durable clinical responses lasting more than 6 months and enabled patients to achieve 5-year overall survival (OS) without subsequent therapy and disease progression6–8. However, a significant proportion of long-term responders still experience progressive disease after a period of response time.
Acquired resistance (AR) refers to a clinical scenario in which cancer initially responds to immunotherapy, but it continues to grow and metastasize to other organs after a period of time. In the epidermal growth factor receptor (EGFR) mutant NSCLC, it is well-known that acquired mutations, including T790M, confer AR to tumors after EGFR tyrosine kinase inhibitor (TKI) treatment9. However, among patients with ICI treatment, more efforts are needed to elucidate which patients will experience AR and how tumor evolution or changes in the immune system lead to AR development. Defects in interferon-receptor signaling and antigen presentation pathways, tumor-associated neoantigen loss, alternate immune checkpoints, and alterations in the tumor microenvironment are believed to be involved in AR mechanisms10–12.
Recently, Gettinger et al.13 presented an impressive single-institution case series of 26 NSCLC patients who experienced AR of the PD-1 blockade. The authors reported the lymph node (LN) as the most common site of AR; their study included 11 cases with only LN progression. The majority of the included patients (88%) showed progression in one or two sites of disease. Overall, 15 (58%) patients received local therapy to sites of AR, while 11 (42%) patients continued immunotherapy beyond progression14. To date, clinical data regarding subsequent treatment strategies and survival according to progression patterns after AR to ICI in NSCLC patients is sparse, especially for those with durable responses.
Therefore, in this study, we conducted a retrospective analysis to investigate the clinical patterns of AR after a durable response to ICIs in NSCLC patients. Additionally, we determined the implications for subsequent therapy in these patients.
Results
Patient characteristics
Of the 125 patients with a durable clinical benefit more than 6 months, 63 (50.4%) patients with AR to ICIs were identified. The baseline clinicopathological characteristics of these patients are summarized in Table 1. The majority (n = 47, 74.6%) of the patients were male, and just over half of the patients were pathologically diagnosed with adenocarcinoma (n = 35, 55.5%). The majority of patients received ICI as first or second-line treatment for metastatic NSCLC (n = 47, 74.6%); 21 (33.3%) and 26 (41.3%) patients received it as first and second-line treatment, respectively. The study included 15 (23.8%) patients with driver mutations. Fifty-two (82.5%) patients received monotherapy, while 11 (17.5%) patients received combination therapy, including five (7.9%) patients with PD-1 and CTLA-4 inhibitors, five (7.9%) patients with PD-L1 and CTLA-4 inhibitors, and one (1.6%) patient with a PD-1 inhibitor and chemotherapy. The median duration of follow-up was 18 months (range, 8–60) and 23 (36.5%) patients were alive at the time of data analysis in December 2018.Table 1 Patient characteristics.
N = 63
Age (years)
Median (range) 64 (34–84)
Sex
Male 47 (74.6)
Female 16 (25.4)
Ethnicity
Asian 63 (100.0)
Smoking
Never smoked 21 (33.3)
Current or ex-smoker 42 (66.7)
Pathology
Adenocarcinoma 35 (55.5)
Poorly differentiated 4 (6.3)
Sarcomatoid 3 (4.8)
Large cell neuroendocrine 2 (3.2)
Squamous 19 (30.2)
Driver mutation
EGFR 11 (17.4)
KRAS 2 (3.2)
ALK 1 (1.6)
ROS1 1 (1.6)
Not identified 48 (76.2)
ICI treatment line
1 21 (33.3)
2 26 (41.3)
≥ 3 16 (25.4)
ICI treatment
PD-1 inhibitor 36 (57.1)
PD-L1 inhibitor 16 (25.4)
PD-1 inhibitor + CTLA-4 inhibitor 5 (7.9)
PD-L1 inhibitor + CTLA-4 inhibitor 5 (7.9)
PD-1 inhibitor + chemotherapy 1 (1.6)
PD-L1 expression
≥ 50% 18 (28.6)
1–49% 10 (15.9)
0% 11 (17.5)
Not available 24 (38.1)
Best objective response
Stable disease 26 (41.3)
Partial response 37 (58.7)
Complete response 0 (0)
EGFR epidermal growth factor receptor, ALK anaplastic lymphoma kinase, PD-1 programmed death 1, PD-L1 programmed death ligand 1, CTLA-4 Cytotoxic T-Lymphocyte Associated Protein 4.
*Data are presented as the median (range) or number (%).
Clinical patterns of ICI failure
Among all the included patients, the median time to AR was 10.7 months. The clinical patterns of AR after ICI treatment are summarized in Table 2 and shown based on their best objective response in Fig. 1.
The most common site of progressive disease was the lungs (38/63, 60.3%), followed by the LNs (31/63, 49.2%), and the brain (6/63, 9.5%). One of fifth (14/63, 22.2%) of patients had only LN progression at the time of AR. Twelve (85.7%) of the 14 patients with LN progression only had achieved PR as their best response, while 2 (14.3%) of the 14 patients achieved SD during ICI treatment (P = 0.04).Table 2 Clinical Patterns of the failure of immune checkpoint inhibitors.
All patients 1st/2nd line ICI ≥ 3rd line ICI P-value
(n = 63) (n = 47) (n = 16)
Previous best response
PR 37 (58.7) 16 (34.0) 6 (37.5) 0.089
SD (≥ 6 months) 26 (41.3) 31 (66.0) 10 (62.5)
Time to acquired resistance
Median (range) 10.7 (6.0–47.2) 10.8 (6.0–47.2) 10.2 (6.4–22.9) 0.052
Overall survival after progression
Median (range) 10.9 (0.0–43.7) 11.5 (0.0–43.7) 9.6 (0.0–30.4) 0.775
Number of progression sites
1 46 (73.0) 36 (76.6) 10 (62.5) 0.553
2 6 (9.5) 4 (8.5) 2 (12.5)
≥ 3 11 (17.5) 7 (14.9) 4 (25.0)
Progression sitea
Lung 38 (60.3) 23 (48.9) 15 (93.8) 0.004
Non-lung visceral organ
Liver 4 (6.3) 2 (4.3) 2 (12.5) 1
Colon 1 (1.6) 1 (2.1) 0 (0)
Adrenal gland 1 (1.6) 1 (2.1) 0 (0)
Heart (pericardium) 2 (3.2) 1 (2.1) 1 (6.2)
Brain 6 (9.5) 5 (10.6) 1 (6.2)
Bone 4 (6.3) 2 (4.3) 2 (12.5) 1
Lymph node 31 24 7 0.265
Neck 5 (7.9) 3 (6.4) 2 (12.5) 0.274
Axilla 2 (3.2) 1 (2.1) 1 (6.2)
Thoracic 20 (32.7) 16 (34.0) 4 (25.0)
Abdomen 4 (6.3) 4 (6.3) 0 (0)
Pre-existence of progression site
New only 13 (20.6) 11 (23.4) 1 (6.2) 0.201
Existing only 43 (68.3) 32 (68.1) 12 (75.0)
Both new and existing 7 (11.1) 4 (8.5) 3 (18.8)
Pattern of progression sites
Lymph node only 14 (22.2) 14 (30.0)) 0 (0) 0.013
Extranodal organs 49 (77.8) 33 (70.0) 16 (100)
Bold values denote statistical significance at the p < 0.05 level
ICI immune checkpoint inhibitors, PR partial response, SD stable disease.
aPatients were included in more than one group based on the site of progression.
Figure 1 Donut plot showing sites of acquired resistance by best objective response to immune checkpoint inhibitors. LN lymph node, PR partial response, SD stable disease.
Next, we evaluated the pattern of failure according to the type of ICI treatment. Less frequent lung progression was observed in patients treated with ICI as first- or second-line treatment than in patients treated with ICI as at least third-line treatment (48.9% vs. 93.8%; P value = 0.039). Progressive disease only in the LNs was observed among the patients who received first- or second line-treatment. There were no statistically significant differences between the two groups regarding the number of progression sites, previous best response, and the pre-existence of progression sites.
The clinical patterns of AR based on the number of progression sites are summarized in Table 3. Fifty-two (82.5%) patients had progression in one or two lesions (oligo-progression group), while 11 (25.4%) patients had progression in three or more lesions (multi-progression group). The lungs were the most frequent sites of progression in both groups. Progression of new lesions only was observed among 12 (23.1%) and 0 (0%) patients with oligo-progression and multi-progression, respectively (P < 0.001). Progression in the LNs only was also more frequent in patients with oligo-progression compared to patients with multi-progression (27.0% vs. 0%, P = 0.103).Table 3 Baseline characteristics based on oligo-progression.
Oligo-progression Multiple progression P-value
(Progression site 1–2) (Progression site 3 ≤)
(n = 52) (n = 11)
Age (years)
Median (range) 64 (34–84) 62 (49–74) 0.752
Sex
Male 38 (73.1) 9 (81.8) 0.714
Female 14 (26.9) 2 (18.2)
Smoking
Never smoked 19 (36.5) 2 (18.2) 0.31
Current or ex-smoker 33 (63.5) 9 (81.8)
Pathology
Squamous 16 (30.8) 3 (27.3) 0.822
Non-Squamous 36 (69.2) 8 (62.7)
ICI treatment line
01-Feb 40 (76.9) 7 (63.6) 0.449
3 ≤ 12 (23.1) 4 (36.4)
Monotherapy
PD-1 inhibitor 27 (51.9) 9 (81.8)
PD-L1 inhibitor 16 (30.8) 0 (0)
Combination therapy
PD-1 inhibitor + chemotherapy 1 (1.9) 0 (0)
PD-1 inhibitor + CTLA-4 inhibitor 3 (5.8) 2 (18.2)
PD-L1 inhibitor + CTLA-4 inhibitor 5 (9.6) 0 (0.0)
Previous response
SD 29 (55.8) 8 (72.7) 0.502
PR 23 (44.2) 3 (27.3)
Progression sitea
Lung 28 (53.8) 10 (90.9) 0.039
Non-lung visceral organ
Liver 2 (3.8) 2 (18.2) 0.275
Colon 1 (1.9) 0 (0)
Adrenal gland 1 (1.9) 0 (0)
Heart (pericardium) 1 (1.9) 1 (9.1)
Brain 5 (9.6) 1 (9.1) 1
Bone 1 (1.9) 3 (27.3) 0.015
Lymph node 14 (23.6) 11 (100) < 0.001
Neck 3 (5.8) 1 (9.1)
Axilla 1 (1.9) 1 (9.1)
Thoracic 10 (15.9) 10 (90.9)
Abdomen 4 (6.3) 0 (0)
Pre-existence of progression site
New only 12 (23.1) 0 (0) < 0.001
Existing only 39 (75.0) 5 (45.5)
Both new and existing 1 (1.9) 6 (54.5)
Pattern of progression sites
Lymph node only 14 (27.0) 0 (0) 0.103
Extranodal organs 38 (73.0) 11 (100.0)
Bold values denote statistical significance at the p < 0.05 level
PR partial response, SD stable disease, PD-1 programmed death 1, PD-L1 programmed death ligand 1, CTLA-4 Cytotoxic T-Lymphocyte Associated Protein 4.
aPatients can be included in more than one group based on the site of progression13.
Survival differences based on the progression patterns
The median OS after AR was 10.9 months. OS after AR was analyzed according to the pattern of progression. When the patients were classified into subgroups (i.e. those who had intrathoracic, extrathoracic [excluding the liver], and liver progression), the median OS after progression was significantly longer in the extrathoracic subgroup than in the thoracic and liver progression subgroups (30.2 months [95% CI, 13.4 to not reached (NR)], 11.7 months [95% CI, 9.5–21.1], and 5.4 months [95% CI, 2.6-NR], respectively, P < 0.001, Fig. 2A). The median OS after progression was significantly longer in the oligo-progression group compared to that in the multiple progression group (18.9 months [95% CI, 10.6-NR] vs. 8.8 months [95% CI, 5.7-NR], P = 0.04, Fig. 2B). The progression patterns were not statistically significant when classified by progression in new lesions (Fig. 2C) nor nodal progression (Fig. 2D).Figure 2 Kaplan–Meier survival curves showing overall survival from the point of acquired resistance for (A) the subgroup that had thoracic, extrathoracic, and liver progression only (B) the subgroup that had one or two progression sites or more than three progression sites (C) the subgroup that had progression from new lesions, existing lesions, and both new and existing lesions (D) the subgroup that had only lymph node and extranodal progression (including the lung).
Subsequent therapy after AR
Among the 63 patients with AR to ICIs, 52 (82.5%) patients received subsequent therapy after progression. Eleven (21.2%) patients received local treatment, including radiotherapy and surgical resection. Forty-one (78.8%) patients underwent systemic therapy after progression, including 25 (48.1%) and 16 (30.8%) patients who received cytotoxic chemotherapy and ICI after progression (Table 4). The median OS of the local therapy, chemotherapy, and ICI groups was 27.4, 23.2, and 29.1 months, respectively; there was no significant difference in survival between these groups (P = 0.787, Fig. 3A). Additionally, there was no significant difference in the PFS between the chemotherapy and the ICI groups (P = 0.723, Fig. 3B).Table 4 Subsequent therapy after progression.
All patients
(n = 52) 1st/2nd line ICI
(n = 40) ≥ 3rd line ICI
(n = 12)
Local therapy (n = 11)
Surgery 2 (3.8) 2 (5.0) 0 (0)
Radiotherapy 7 (13.5) 6 (15.0) 1 (8.3)
Gamma-knife surgery 2 (3.8) 2 (5.0)) 0 (0)
Systemic therapy (n = 41)
Immunotherapy 16 (30.8) 16 (40.0) 0 (0.0)
Chemotherapy 25 (48.1) 16 (40.0) 9 (75.0)
All patients
(n = 52) Oligo-progression
(Progression site 1–2)
(n = 43) Multiple progression
(Progression site 3 ≤)
(n = 9)
Local therapy (n = 11)
Surgery 2 (3.8) 2 (4.7) 0 (0)
Radiotherapy 7 (13.5) 6 (14.0) 1 (11.1)
Gamma-knife surgery 2 (3.8) 2 (4.7) 0 (0)
Systemic therapy (n = 41)
Immunotherapy 16 (30.8) 14 (32.6) 2 (22.2)
chemotherapy 25 (48.1) 19 (44.2) 6 (66.7)
Local therapy (n = 11) Surgery Colon mass excision (1)
Axilla LN excision (1)
Radiotherapy Abdomen LN (2)
Neck & SCN LN (1)
Lung mass (2)
Bone (2)
Gamma-knife surgery Brain (2)
ICI immune checkpoint inhibitors.
Figure 3 Kaplan–Meier survival curves showing (A) overall survival from the point of acquired resistance based on the subgroups of subsequent treatment (B) progression free survival based on the subsequent treatment.
Discussion
In this study, after a median time of 10.4 months, patients who had a durable clinical benefit experienced AR. The majority of these patients (52/63, 82.5%) had progressive disease in one or two sites. Progression in the LNs only was observed in 22.2% patients at the time of AR; such patients received ICI as first or second-line treatment. Most (12/14, 85.7%) patients with progression in the LNs only had objective tumor shrinkage, partial response according to RECIST, during ICI treatment. Among patients with oligo-progression (n = 52), progression of the LNs only (27.0%) or appearance of new lesions without evident progression of pre-existing lesions (23.1%) was observed. The patterns of progression observed in this cohort of patients with NSCLC at the time of AR are very unique considering that most patients treated in the conventional chemotherapy era develop systemic progression including pre-existing diseases. Even after having AR, patients with oligo-progression could be treated with local ablative therapy or continued ICI beyond AR. In the survival analysis, there was significantly longer OS among the oligo-progressors compared to that among systemic or multiple site progressors. We observed no significant difference in terms of PFS and OS between patients with subsequent chemotherapy and those with continuation of ICI beyond progression.
A notable finding in our study was that a significant portion of patients with AR to ICIs had progression of the LNs only, with sustained anti-cancer efficacy of ICI in pre-existing lesions. Among patients with a PR response with ICI (n = 37, 58.7%), 12 (32.4%) patients had progression of the LNs only. In the previous study by Gettinger et al. it was also reported that 42% of NSCLC patients who achieved PR after ICI treatment had AR limited to the LNs11. The study also suggested that the malignant LN environment may lead to the immunosuppressive evolution of cells within the node.
It should be also noted that that patients with oligo-progression showed prolonged OS compared to those with multi-progression after AR in our study. Potential hypotheses for this finding might be the “the cancer-immunity cycle”15. Tumors in still “immune surveillance active” hosts are not able to proliferate or metastasize to other organs unless they obtain the novel phenotype of immune evasion. Therefore, it is easily conceivable that lung cancer clones in the progressive site might have evolved to escape host immune surveillance with either loss of heterozygosity in human leukocyte antigens or depletion of the expressed neoantigens16.
In this study, physicians preferred local therapy and immunotherapy beyond progression for patients with oligo-progression. For NSCLC, there was an interesting retrospective report from the phase III OAK study that atezolizumab showed acceptable efficacy and safety after progression with patients with good performance17. To date, ICI has been reported to show post-progression efficacies in a limited subset of patients including those with metastatic urothelial carcinoma, renal cell carcinoma and melanoma, and NSCLC18–22. However, whether treatment beyond progression will be effective is not yet elucidated in patients with AR. Gettinger et al. reported that 11 NSCLC patients continued immunotherapy beyond AR13. Adam LC et al. reported an AR case of successful local control with cryotherapy combined with immunotherapy beyond progression23. Further analysis will help to define the clinical benefit for NSCLC patients with a durable response treated with ICI beyond progression.
There are several limitations to this study. First, this was a retrospective analysis. As not many patients showed a durable response to ICI, only a small number of patients were included in the study, resulting in limited statistical power. Therefore, the small study size prohibited us from performing comparisons between the different subgroups. Second, the study population was very diverse, including not only patients with PD-1 inhibitor or PD-L1 inhibitor monotherapy, but also patients with combination therapy including cytotoxic drugs or CTLA-4 inhibitors. Third, although the PD-L1 expression profile is a very important prognostic factor, our study included the PD-L1 profile utilizing three different anti-PD-L1 antibodies (22C3, E1L3N, and SP263). As most of the patients (81.0%) were involved in clinical trials, we were not able to ascertain the immunohistochemistry profiles for some patients, due to patient information protection regulations. Besides, information on co-medication such as antibiotics, corticosteroids, opioids, or proton pump inhibitors, which can affect ICI response, was not fully available. Lastly, there may be bias in the selection of subsequent therapy, as each individual physician was responsible for selecting the appropriate treatment.
Despite these limitations, our study described the clinical features and patterns of AR in detail. To our knowledge, this is the first study to show survival differences based on progression patterns. We believe that this report may provide useful information to clinicians regarding advanced NSCLC patients; additionally, it highlights the implications of subsequent therapy after AR.
In conclusion, advanced NSCLC patients who had durable responses (> 6 months) showed unique patterns of progression with high rates of progression among the LN only, in addition to oligo-progression. Local treatment and/or continuation of ICIs beyond AR might be an effective option for those patients. Further large-scale prospective studies are required to confirm these findings.
Methods
Design, patients, and data collection
We retrospectively reviewed the records of patients diagnosed with NSCLC and treated with inhibitors of PD-1 and PD-L1 at the Seoul National University Hospital (SNUH) and Seoul National University Bundang Hospital (SNUBH) between January 1, 2011 and November 31, 2018.
Adults without a previous history of severe systemic disease or autoimmune diseases who received PD-1/PD-L1 blockade alone or with cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor or chemotherapy over the course of disease were included.
Patient classification and outcome measures
The patients were classified into the following subgroups: those who had intrathoracic, extrathoracic [excluding the liver], and liver progression. AR after durable response was defined as disease progression after 6 months with the best response of the stable disease, partial response, or complete response according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criterion. Imaging studies included Computed tomography scan and Magnetic resonance imaging and were independently reviewed by two observers. Progression-free survival (PFS) was calculated from the ICI treatment initiation date to the date of disease progression using the RECIST v1.1 criteria24, as confirmed by imaging, death, or the last follow-up date, if censored. OS was measured from the initiation of ICI treatment until death or the last follow-up date, if censored.
Statistical analyses
Continuous variables were compared using the Students t-test or the Mann–Whitney U-test, whereas categorical variables were compared using the chi-squared or Fisher exact tests. Survival analyses were conducted according to the Kaplan–Meier method using the log-rank test. All tests were two-sided and p-values < 0.05 were considered to be statistically significant. For survival analysis, R version 3.4.3 software (R Development Core Team, https://www.r-project.org/) was used for computation.
Ethics
All the included patients provided written, informed consent for data collection before treatment. The research team conducted retrospective analyses on cohort data. The institutional review boards of SNUH and SNUBH approved the study protocol (IRB number: B-2004-606-105). All procedures were carried out in accordance with the ethical standards of the institutional research ethics committee and the Helsinki declaration revised in 2013 by the World Medical Association.
Supplementary Information
Supplementary Table 1.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material availlable at 10.1038/s41598-021-81666-x.
Acknowledgements
This study was supported by the Grants from the SNUBH Research Fund (Grant Number: 13-2017-002 to SH Kim).
Author contributions
Writing: J.Y.H. Data acquisition: J.Y.H and S.H.Y, Supervision and review: C.O, M.K., B.K., T.M.K., D.K., D.S.H , K.J.S., S.H.K., Y.J.K. and J.S.L. Editing: J.Y.H. and S.H.K.
Competing interests
The authors declare no competing interests. | NIVOLUMAB | DrugsGivenReaction | CC BY | 33510255 | 18,970,334 | 2021-01-28 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thyroiditis'. | Clinical pattern of failure after a durable response to immune check inhibitors in non-small cell lung cancer patients.
Although immune checkpoint inhibitors (ICIs) can induce durable responses in non-small-cell lung cancer (NSCLC) patients, a significant proportion of responders still experience progressive disease after a period of response. Limited data are available on the clinical patterns of acquired resistance (AR) to ICIs. Clinical and radiologic data from 125 NSCLC patients treated with anti-PD-1 or PD-L1 antibodies between 2011 and 2018 at two tertiary academic institutions were retrospectively reviewed. Overall, 63 (50.4%) patients experienced AR after ICI treatment in a median of 10.7 months. Among the 13 patients with a partial response with ICI, 12 (32.4%) had only lymph node progression. Most patients (n = 52, 82.5%) had one or two sites with progression (oligo-progression). The median overall survival (OS) after progression was significantly longer in the extrathoracic group than in the thoracic and liver progression groups (30.2 months [95% confidence interval (CI), 13.4 to not reached (NR)], 11.7 months [95% CI, 9.5-21.1], and 5.4 months [95% CI, 2.6-NR], respectively, P < 0.001). Patients with oligo-progression had significantly longer OS after AR than did the multi-progression patients (18.9 months [95% CI, 10.6-NR] vs. 8.8 months [95% CI, 5.7-NR], P = 0.04). No significant difference in progression-free survival was observed between the subsequent chemotherapy and the ICI after AR groups (P = 0.723). Patients with AR after ICI treatment had a unique progression pattern with oligo-progression and high rates of progression only in the lymph nodes. Local treatment and/or continuation of ICIs beyond AR might be an effective option.
Introduction
Immune checkpoint inhibitors (ICIs), including anti- programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) antibodies, represent a breakthrough in the treatment of non-small-cell lung cancer (NSCLC). Previous studies have shown that high levels of PD-L1 expression on tumors and/or immune cells by immunohistochemistry are associated with improved clinical efficacy when compared with low levels or negative PD-L11–6. In patients with pretreated advanced NSCLC, ICI monotherapy resulted in durable clinical responses lasting more than 6 months and enabled patients to achieve 5-year overall survival (OS) without subsequent therapy and disease progression6–8. However, a significant proportion of long-term responders still experience progressive disease after a period of response time.
Acquired resistance (AR) refers to a clinical scenario in which cancer initially responds to immunotherapy, but it continues to grow and metastasize to other organs after a period of time. In the epidermal growth factor receptor (EGFR) mutant NSCLC, it is well-known that acquired mutations, including T790M, confer AR to tumors after EGFR tyrosine kinase inhibitor (TKI) treatment9. However, among patients with ICI treatment, more efforts are needed to elucidate which patients will experience AR and how tumor evolution or changes in the immune system lead to AR development. Defects in interferon-receptor signaling and antigen presentation pathways, tumor-associated neoantigen loss, alternate immune checkpoints, and alterations in the tumor microenvironment are believed to be involved in AR mechanisms10–12.
Recently, Gettinger et al.13 presented an impressive single-institution case series of 26 NSCLC patients who experienced AR of the PD-1 blockade. The authors reported the lymph node (LN) as the most common site of AR; their study included 11 cases with only LN progression. The majority of the included patients (88%) showed progression in one or two sites of disease. Overall, 15 (58%) patients received local therapy to sites of AR, while 11 (42%) patients continued immunotherapy beyond progression14. To date, clinical data regarding subsequent treatment strategies and survival according to progression patterns after AR to ICI in NSCLC patients is sparse, especially for those with durable responses.
Therefore, in this study, we conducted a retrospective analysis to investigate the clinical patterns of AR after a durable response to ICIs in NSCLC patients. Additionally, we determined the implications for subsequent therapy in these patients.
Results
Patient characteristics
Of the 125 patients with a durable clinical benefit more than 6 months, 63 (50.4%) patients with AR to ICIs were identified. The baseline clinicopathological characteristics of these patients are summarized in Table 1. The majority (n = 47, 74.6%) of the patients were male, and just over half of the patients were pathologically diagnosed with adenocarcinoma (n = 35, 55.5%). The majority of patients received ICI as first or second-line treatment for metastatic NSCLC (n = 47, 74.6%); 21 (33.3%) and 26 (41.3%) patients received it as first and second-line treatment, respectively. The study included 15 (23.8%) patients with driver mutations. Fifty-two (82.5%) patients received monotherapy, while 11 (17.5%) patients received combination therapy, including five (7.9%) patients with PD-1 and CTLA-4 inhibitors, five (7.9%) patients with PD-L1 and CTLA-4 inhibitors, and one (1.6%) patient with a PD-1 inhibitor and chemotherapy. The median duration of follow-up was 18 months (range, 8–60) and 23 (36.5%) patients were alive at the time of data analysis in December 2018.Table 1 Patient characteristics.
N = 63
Age (years)
Median (range) 64 (34–84)
Sex
Male 47 (74.6)
Female 16 (25.4)
Ethnicity
Asian 63 (100.0)
Smoking
Never smoked 21 (33.3)
Current or ex-smoker 42 (66.7)
Pathology
Adenocarcinoma 35 (55.5)
Poorly differentiated 4 (6.3)
Sarcomatoid 3 (4.8)
Large cell neuroendocrine 2 (3.2)
Squamous 19 (30.2)
Driver mutation
EGFR 11 (17.4)
KRAS 2 (3.2)
ALK 1 (1.6)
ROS1 1 (1.6)
Not identified 48 (76.2)
ICI treatment line
1 21 (33.3)
2 26 (41.3)
≥ 3 16 (25.4)
ICI treatment
PD-1 inhibitor 36 (57.1)
PD-L1 inhibitor 16 (25.4)
PD-1 inhibitor + CTLA-4 inhibitor 5 (7.9)
PD-L1 inhibitor + CTLA-4 inhibitor 5 (7.9)
PD-1 inhibitor + chemotherapy 1 (1.6)
PD-L1 expression
≥ 50% 18 (28.6)
1–49% 10 (15.9)
0% 11 (17.5)
Not available 24 (38.1)
Best objective response
Stable disease 26 (41.3)
Partial response 37 (58.7)
Complete response 0 (0)
EGFR epidermal growth factor receptor, ALK anaplastic lymphoma kinase, PD-1 programmed death 1, PD-L1 programmed death ligand 1, CTLA-4 Cytotoxic T-Lymphocyte Associated Protein 4.
*Data are presented as the median (range) or number (%).
Clinical patterns of ICI failure
Among all the included patients, the median time to AR was 10.7 months. The clinical patterns of AR after ICI treatment are summarized in Table 2 and shown based on their best objective response in Fig. 1.
The most common site of progressive disease was the lungs (38/63, 60.3%), followed by the LNs (31/63, 49.2%), and the brain (6/63, 9.5%). One of fifth (14/63, 22.2%) of patients had only LN progression at the time of AR. Twelve (85.7%) of the 14 patients with LN progression only had achieved PR as their best response, while 2 (14.3%) of the 14 patients achieved SD during ICI treatment (P = 0.04).Table 2 Clinical Patterns of the failure of immune checkpoint inhibitors.
All patients 1st/2nd line ICI ≥ 3rd line ICI P-value
(n = 63) (n = 47) (n = 16)
Previous best response
PR 37 (58.7) 16 (34.0) 6 (37.5) 0.089
SD (≥ 6 months) 26 (41.3) 31 (66.0) 10 (62.5)
Time to acquired resistance
Median (range) 10.7 (6.0–47.2) 10.8 (6.0–47.2) 10.2 (6.4–22.9) 0.052
Overall survival after progression
Median (range) 10.9 (0.0–43.7) 11.5 (0.0–43.7) 9.6 (0.0–30.4) 0.775
Number of progression sites
1 46 (73.0) 36 (76.6) 10 (62.5) 0.553
2 6 (9.5) 4 (8.5) 2 (12.5)
≥ 3 11 (17.5) 7 (14.9) 4 (25.0)
Progression sitea
Lung 38 (60.3) 23 (48.9) 15 (93.8) 0.004
Non-lung visceral organ
Liver 4 (6.3) 2 (4.3) 2 (12.5) 1
Colon 1 (1.6) 1 (2.1) 0 (0)
Adrenal gland 1 (1.6) 1 (2.1) 0 (0)
Heart (pericardium) 2 (3.2) 1 (2.1) 1 (6.2)
Brain 6 (9.5) 5 (10.6) 1 (6.2)
Bone 4 (6.3) 2 (4.3) 2 (12.5) 1
Lymph node 31 24 7 0.265
Neck 5 (7.9) 3 (6.4) 2 (12.5) 0.274
Axilla 2 (3.2) 1 (2.1) 1 (6.2)
Thoracic 20 (32.7) 16 (34.0) 4 (25.0)
Abdomen 4 (6.3) 4 (6.3) 0 (0)
Pre-existence of progression site
New only 13 (20.6) 11 (23.4) 1 (6.2) 0.201
Existing only 43 (68.3) 32 (68.1) 12 (75.0)
Both new and existing 7 (11.1) 4 (8.5) 3 (18.8)
Pattern of progression sites
Lymph node only 14 (22.2) 14 (30.0)) 0 (0) 0.013
Extranodal organs 49 (77.8) 33 (70.0) 16 (100)
Bold values denote statistical significance at the p < 0.05 level
ICI immune checkpoint inhibitors, PR partial response, SD stable disease.
aPatients were included in more than one group based on the site of progression.
Figure 1 Donut plot showing sites of acquired resistance by best objective response to immune checkpoint inhibitors. LN lymph node, PR partial response, SD stable disease.
Next, we evaluated the pattern of failure according to the type of ICI treatment. Less frequent lung progression was observed in patients treated with ICI as first- or second-line treatment than in patients treated with ICI as at least third-line treatment (48.9% vs. 93.8%; P value = 0.039). Progressive disease only in the LNs was observed among the patients who received first- or second line-treatment. There were no statistically significant differences between the two groups regarding the number of progression sites, previous best response, and the pre-existence of progression sites.
The clinical patterns of AR based on the number of progression sites are summarized in Table 3. Fifty-two (82.5%) patients had progression in one or two lesions (oligo-progression group), while 11 (25.4%) patients had progression in three or more lesions (multi-progression group). The lungs were the most frequent sites of progression in both groups. Progression of new lesions only was observed among 12 (23.1%) and 0 (0%) patients with oligo-progression and multi-progression, respectively (P < 0.001). Progression in the LNs only was also more frequent in patients with oligo-progression compared to patients with multi-progression (27.0% vs. 0%, P = 0.103).Table 3 Baseline characteristics based on oligo-progression.
Oligo-progression Multiple progression P-value
(Progression site 1–2) (Progression site 3 ≤)
(n = 52) (n = 11)
Age (years)
Median (range) 64 (34–84) 62 (49–74) 0.752
Sex
Male 38 (73.1) 9 (81.8) 0.714
Female 14 (26.9) 2 (18.2)
Smoking
Never smoked 19 (36.5) 2 (18.2) 0.31
Current or ex-smoker 33 (63.5) 9 (81.8)
Pathology
Squamous 16 (30.8) 3 (27.3) 0.822
Non-Squamous 36 (69.2) 8 (62.7)
ICI treatment line
01-Feb 40 (76.9) 7 (63.6) 0.449
3 ≤ 12 (23.1) 4 (36.4)
Monotherapy
PD-1 inhibitor 27 (51.9) 9 (81.8)
PD-L1 inhibitor 16 (30.8) 0 (0)
Combination therapy
PD-1 inhibitor + chemotherapy 1 (1.9) 0 (0)
PD-1 inhibitor + CTLA-4 inhibitor 3 (5.8) 2 (18.2)
PD-L1 inhibitor + CTLA-4 inhibitor 5 (9.6) 0 (0.0)
Previous response
SD 29 (55.8) 8 (72.7) 0.502
PR 23 (44.2) 3 (27.3)
Progression sitea
Lung 28 (53.8) 10 (90.9) 0.039
Non-lung visceral organ
Liver 2 (3.8) 2 (18.2) 0.275
Colon 1 (1.9) 0 (0)
Adrenal gland 1 (1.9) 0 (0)
Heart (pericardium) 1 (1.9) 1 (9.1)
Brain 5 (9.6) 1 (9.1) 1
Bone 1 (1.9) 3 (27.3) 0.015
Lymph node 14 (23.6) 11 (100) < 0.001
Neck 3 (5.8) 1 (9.1)
Axilla 1 (1.9) 1 (9.1)
Thoracic 10 (15.9) 10 (90.9)
Abdomen 4 (6.3) 0 (0)
Pre-existence of progression site
New only 12 (23.1) 0 (0) < 0.001
Existing only 39 (75.0) 5 (45.5)
Both new and existing 1 (1.9) 6 (54.5)
Pattern of progression sites
Lymph node only 14 (27.0) 0 (0) 0.103
Extranodal organs 38 (73.0) 11 (100.0)
Bold values denote statistical significance at the p < 0.05 level
PR partial response, SD stable disease, PD-1 programmed death 1, PD-L1 programmed death ligand 1, CTLA-4 Cytotoxic T-Lymphocyte Associated Protein 4.
aPatients can be included in more than one group based on the site of progression13.
Survival differences based on the progression patterns
The median OS after AR was 10.9 months. OS after AR was analyzed according to the pattern of progression. When the patients were classified into subgroups (i.e. those who had intrathoracic, extrathoracic [excluding the liver], and liver progression), the median OS after progression was significantly longer in the extrathoracic subgroup than in the thoracic and liver progression subgroups (30.2 months [95% CI, 13.4 to not reached (NR)], 11.7 months [95% CI, 9.5–21.1], and 5.4 months [95% CI, 2.6-NR], respectively, P < 0.001, Fig. 2A). The median OS after progression was significantly longer in the oligo-progression group compared to that in the multiple progression group (18.9 months [95% CI, 10.6-NR] vs. 8.8 months [95% CI, 5.7-NR], P = 0.04, Fig. 2B). The progression patterns were not statistically significant when classified by progression in new lesions (Fig. 2C) nor nodal progression (Fig. 2D).Figure 2 Kaplan–Meier survival curves showing overall survival from the point of acquired resistance for (A) the subgroup that had thoracic, extrathoracic, and liver progression only (B) the subgroup that had one or two progression sites or more than three progression sites (C) the subgroup that had progression from new lesions, existing lesions, and both new and existing lesions (D) the subgroup that had only lymph node and extranodal progression (including the lung).
Subsequent therapy after AR
Among the 63 patients with AR to ICIs, 52 (82.5%) patients received subsequent therapy after progression. Eleven (21.2%) patients received local treatment, including radiotherapy and surgical resection. Forty-one (78.8%) patients underwent systemic therapy after progression, including 25 (48.1%) and 16 (30.8%) patients who received cytotoxic chemotherapy and ICI after progression (Table 4). The median OS of the local therapy, chemotherapy, and ICI groups was 27.4, 23.2, and 29.1 months, respectively; there was no significant difference in survival between these groups (P = 0.787, Fig. 3A). Additionally, there was no significant difference in the PFS between the chemotherapy and the ICI groups (P = 0.723, Fig. 3B).Table 4 Subsequent therapy after progression.
All patients
(n = 52) 1st/2nd line ICI
(n = 40) ≥ 3rd line ICI
(n = 12)
Local therapy (n = 11)
Surgery 2 (3.8) 2 (5.0) 0 (0)
Radiotherapy 7 (13.5) 6 (15.0) 1 (8.3)
Gamma-knife surgery 2 (3.8) 2 (5.0)) 0 (0)
Systemic therapy (n = 41)
Immunotherapy 16 (30.8) 16 (40.0) 0 (0.0)
Chemotherapy 25 (48.1) 16 (40.0) 9 (75.0)
All patients
(n = 52) Oligo-progression
(Progression site 1–2)
(n = 43) Multiple progression
(Progression site 3 ≤)
(n = 9)
Local therapy (n = 11)
Surgery 2 (3.8) 2 (4.7) 0 (0)
Radiotherapy 7 (13.5) 6 (14.0) 1 (11.1)
Gamma-knife surgery 2 (3.8) 2 (4.7) 0 (0)
Systemic therapy (n = 41)
Immunotherapy 16 (30.8) 14 (32.6) 2 (22.2)
chemotherapy 25 (48.1) 19 (44.2) 6 (66.7)
Local therapy (n = 11) Surgery Colon mass excision (1)
Axilla LN excision (1)
Radiotherapy Abdomen LN (2)
Neck & SCN LN (1)
Lung mass (2)
Bone (2)
Gamma-knife surgery Brain (2)
ICI immune checkpoint inhibitors.
Figure 3 Kaplan–Meier survival curves showing (A) overall survival from the point of acquired resistance based on the subgroups of subsequent treatment (B) progression free survival based on the subsequent treatment.
Discussion
In this study, after a median time of 10.4 months, patients who had a durable clinical benefit experienced AR. The majority of these patients (52/63, 82.5%) had progressive disease in one or two sites. Progression in the LNs only was observed in 22.2% patients at the time of AR; such patients received ICI as first or second-line treatment. Most (12/14, 85.7%) patients with progression in the LNs only had objective tumor shrinkage, partial response according to RECIST, during ICI treatment. Among patients with oligo-progression (n = 52), progression of the LNs only (27.0%) or appearance of new lesions without evident progression of pre-existing lesions (23.1%) was observed. The patterns of progression observed in this cohort of patients with NSCLC at the time of AR are very unique considering that most patients treated in the conventional chemotherapy era develop systemic progression including pre-existing diseases. Even after having AR, patients with oligo-progression could be treated with local ablative therapy or continued ICI beyond AR. In the survival analysis, there was significantly longer OS among the oligo-progressors compared to that among systemic or multiple site progressors. We observed no significant difference in terms of PFS and OS between patients with subsequent chemotherapy and those with continuation of ICI beyond progression.
A notable finding in our study was that a significant portion of patients with AR to ICIs had progression of the LNs only, with sustained anti-cancer efficacy of ICI in pre-existing lesions. Among patients with a PR response with ICI (n = 37, 58.7%), 12 (32.4%) patients had progression of the LNs only. In the previous study by Gettinger et al. it was also reported that 42% of NSCLC patients who achieved PR after ICI treatment had AR limited to the LNs11. The study also suggested that the malignant LN environment may lead to the immunosuppressive evolution of cells within the node.
It should be also noted that that patients with oligo-progression showed prolonged OS compared to those with multi-progression after AR in our study. Potential hypotheses for this finding might be the “the cancer-immunity cycle”15. Tumors in still “immune surveillance active” hosts are not able to proliferate or metastasize to other organs unless they obtain the novel phenotype of immune evasion. Therefore, it is easily conceivable that lung cancer clones in the progressive site might have evolved to escape host immune surveillance with either loss of heterozygosity in human leukocyte antigens or depletion of the expressed neoantigens16.
In this study, physicians preferred local therapy and immunotherapy beyond progression for patients with oligo-progression. For NSCLC, there was an interesting retrospective report from the phase III OAK study that atezolizumab showed acceptable efficacy and safety after progression with patients with good performance17. To date, ICI has been reported to show post-progression efficacies in a limited subset of patients including those with metastatic urothelial carcinoma, renal cell carcinoma and melanoma, and NSCLC18–22. However, whether treatment beyond progression will be effective is not yet elucidated in patients with AR. Gettinger et al. reported that 11 NSCLC patients continued immunotherapy beyond AR13. Adam LC et al. reported an AR case of successful local control with cryotherapy combined with immunotherapy beyond progression23. Further analysis will help to define the clinical benefit for NSCLC patients with a durable response treated with ICI beyond progression.
There are several limitations to this study. First, this was a retrospective analysis. As not many patients showed a durable response to ICI, only a small number of patients were included in the study, resulting in limited statistical power. Therefore, the small study size prohibited us from performing comparisons between the different subgroups. Second, the study population was very diverse, including not only patients with PD-1 inhibitor or PD-L1 inhibitor monotherapy, but also patients with combination therapy including cytotoxic drugs or CTLA-4 inhibitors. Third, although the PD-L1 expression profile is a very important prognostic factor, our study included the PD-L1 profile utilizing three different anti-PD-L1 antibodies (22C3, E1L3N, and SP263). As most of the patients (81.0%) were involved in clinical trials, we were not able to ascertain the immunohistochemistry profiles for some patients, due to patient information protection regulations. Besides, information on co-medication such as antibiotics, corticosteroids, opioids, or proton pump inhibitors, which can affect ICI response, was not fully available. Lastly, there may be bias in the selection of subsequent therapy, as each individual physician was responsible for selecting the appropriate treatment.
Despite these limitations, our study described the clinical features and patterns of AR in detail. To our knowledge, this is the first study to show survival differences based on progression patterns. We believe that this report may provide useful information to clinicians regarding advanced NSCLC patients; additionally, it highlights the implications of subsequent therapy after AR.
In conclusion, advanced NSCLC patients who had durable responses (> 6 months) showed unique patterns of progression with high rates of progression among the LN only, in addition to oligo-progression. Local treatment and/or continuation of ICIs beyond AR might be an effective option for those patients. Further large-scale prospective studies are required to confirm these findings.
Methods
Design, patients, and data collection
We retrospectively reviewed the records of patients diagnosed with NSCLC and treated with inhibitors of PD-1 and PD-L1 at the Seoul National University Hospital (SNUH) and Seoul National University Bundang Hospital (SNUBH) between January 1, 2011 and November 31, 2018.
Adults without a previous history of severe systemic disease or autoimmune diseases who received PD-1/PD-L1 blockade alone or with cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor or chemotherapy over the course of disease were included.
Patient classification and outcome measures
The patients were classified into the following subgroups: those who had intrathoracic, extrathoracic [excluding the liver], and liver progression. AR after durable response was defined as disease progression after 6 months with the best response of the stable disease, partial response, or complete response according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criterion. Imaging studies included Computed tomography scan and Magnetic resonance imaging and were independently reviewed by two observers. Progression-free survival (PFS) was calculated from the ICI treatment initiation date to the date of disease progression using the RECIST v1.1 criteria24, as confirmed by imaging, death, or the last follow-up date, if censored. OS was measured from the initiation of ICI treatment until death or the last follow-up date, if censored.
Statistical analyses
Continuous variables were compared using the Students t-test or the Mann–Whitney U-test, whereas categorical variables were compared using the chi-squared or Fisher exact tests. Survival analyses were conducted according to the Kaplan–Meier method using the log-rank test. All tests were two-sided and p-values < 0.05 were considered to be statistically significant. For survival analysis, R version 3.4.3 software (R Development Core Team, https://www.r-project.org/) was used for computation.
Ethics
All the included patients provided written, informed consent for data collection before treatment. The research team conducted retrospective analyses on cohort data. The institutional review boards of SNUH and SNUBH approved the study protocol (IRB number: B-2004-606-105). All procedures were carried out in accordance with the ethical standards of the institutional research ethics committee and the Helsinki declaration revised in 2013 by the World Medical Association.
Supplementary Information
Supplementary Table 1.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
The online version contains supplementary material availlable at 10.1038/s41598-021-81666-x.
Acknowledgements
This study was supported by the Grants from the SNUBH Research Fund (Grant Number: 13-2017-002 to SH Kim).
Author contributions
Writing: J.Y.H. Data acquisition: J.Y.H and S.H.Y, Supervision and review: C.O, M.K., B.K., T.M.K., D.K., D.S.H , K.J.S., S.H.K., Y.J.K. and J.S.L. Editing: J.Y.H. and S.H.K.
Competing interests
The authors declare no competing interests. | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY | 33510255 | 18,971,109 | 2021-01-28 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal exposure during pregnancy'. | Pregnancy-Associated Chest Pain: A Case of Spontaneous Coronary Artery Dissection.
Spontaneous Coronary Artery Dissection (SCAD) is an important cause of myocardial infarction that typically affects women without traditional cardiovascular risk factors. It is the most common cause of myocardial infarction in pregnant and postpartum women. SCAD is often underdiagnosed due to the lack of clinician familiarity, and patients with pregnancy-associated SCAD often have more severe clinical presentations than those without. We present a case of SCAD in a multiparous woman who presented with acute chest pain in the postpartum period.
1. Introduction
SCAD is a rare but important cause of myocardial infarction (MI) and sudden cardiac death. SCAD is defined as an epicardial coronary dissection not associated with atherosclerosis, trauma, or iatrogenic injury and is the most common cause of pregnancy-associated and postpartum MI [1]. SCAD typically occurs in women without traditional atherosclerotic cardiovascular risk factors, and the mechanism of injury is thought to be coronary artery obstruction from an intramural hematoma or intimal disruption [2]. Risk factors for SCAD are fibromuscular dysplasia, connective tissue disease, physical stress, emotional stress, pregnancy, and multiparity. It is hypothesized that hormonal changes during pregnancy weaken the coronary arterial vessel walls; multiparous women can accumulate these changes over several pregnancies [2].
Patients with pregnancy-associated SCAD often have more acute presentations and high-risk features than patients with non-pregnancy-associated SCAD. Most cases of pregnancy-associated SCAD occur in the first month postpartum, with the majority in the first week following delivery [3]. It is important to recognize SCAD in clinical practice as the population affected, and management is different than other causes of MI.
2. Case Report
A 44-year-old gravida 6 para 4 postpartum woman presented to the emergency department (ED) complaining of substernal chest pain. That afternoon, she experienced sudden-onset severe left-sided chest pain radiating to her back and shoulder. She had been discharged four days prior after induction of labor for chronic hypertension with an uncomplicated vaginal birth. Her medical history was notable only for hypertension, for which she took metoprolol. She was maintained on metoprolol with good blood pressure control for the duration of her pregnancy and after induction. The day prior to admission she was under significant emotional distress after her infant was hospitalized with hyperbilirubinemia.
In the ED, the patient was afebrile, her blood pressure was 164/101 mm Hg, her heart rate was 60 beats per minute, and she was breathing 16 breaths per minute. Her cardiovascular examination was unremarkable with normal heart sounds with no murmurs, rubs, or gallops and no jugular venous distension. Her lungs were clear, her abdomen was soft, and she had no extremity edema. Her complete blood count and comprehensive metabolic panel results were within normal limits. Her initial troponin I was 0.41 ng/mL (reference range, <0.04 ng/mL), and her electrocardiogram (ECG) (Figure 1) was significant for ST elevation in leads V2-V5 consistent with an anterior ST-segment elevation myocardial infarction (STEMI). Her chest X-ray showed normal mediastinum, no signs of cardiomegaly, and clear lungs.
Given the concern for acute coronary syndrome (ACS), the patient was emergently taken to the cardiac catheterization lab. Her coronary angiogram showed haziness of the midleft anterior descending (LAD) artery followed by an abrupt change in arterial caliber extending to the distal LAD and diagonal branches (Figure 2(a)). There was no clear visualization of a dissection flap, but there was a visible long segment of diffuse vessel narrowing in the mid to distal LAD highly suspicious for coronary dissection. Contrast flow in the distal vessel was normal (TIMI 3), and there were no luminal changes with the administration of intracoronary nitroglycerin. There was no angiographic evidence of atherosclerotic disease in any of her coronary arteries, and no evidence of narrowing in the coronary arteries outside of the LAD. Her chest pain was resolved during the procedure, and her ECG showed normalization of her ST elevation. Given the patient's hemodynamic stability, normal blood flow in the distal LAD, resolution of chest pain, and suspicion for dissection, she was managed conservatively.
She was started on IV nitroglycerin for hypertension, metoprolol, and dual antiplatelet therapy with aspirin and clopidogrel and then transferred to the coronary care unit for close observation. Her transthoracic echocardiogram showed normal left ventricular function with an ejection fraction of 68% and hypokinetic septal and apical walls in the distribution of the LAD. Her repeat ECG (Figure 3) showed the expected evolution of her STEMI with QS waves and T-wave inversions seen in leads V2-V5. She was weaned off the nitroglycerin and transitioned to captopril and nifedipine for strict blood pressure control and safety with breastfeeding.
She remained chest-pain free during the course of the hospitalization and underwent a repeat angiogram to evaluate for the progression of disease given the diagnostic uncertainty. Her repeat angiogram on day 6 of hospitalization showed complete resolution of the LAD lesion (Figure 2(c)) consistent with dissection. Compared to the initial angiogram, the area of haziness was no longer present, and the vessel tapered appropriately towards the apical LAD. However, a new tubular narrowing with abrupt vessel caliber change (Figure 2(d)) was noted in the midposterior descending artery (PDA), compared to her initial angiogram (Figure 2(b)) with normal flow and no clear dissection flap. This event was concerning for a new dissection event. The patient was asymptomatic throughout her hospitalization and was discharged home with close obstetric, primary care, and cardiology outpatient follow-up.
3. Discussion
In this postpartum woman presenting with a STEMI with angiographic findings suggestive of coronary dissection and no evidence of atherosclerotic disease, a diagnosis of SCAD was made. SCAD commonly presents as ACS with ST-segment changes, and early angiography should be performed to confirm the diagnosis, assess the coronary anatomy, and facilitate revascularization when necessary [2–4]. SCAD is often misdiagnosed and a research group recently published a flowchart to aid in the diagnosis [5]. Angiographically, SCAD has three main classifications: Type 1 is identified by contrast staining showing multiple lumens, Type 2 is an abrupt change in vessel caliber with diffuse tubular stenoses of varying length, and Type 3 is a focal stenosis that mimics atherosclerosis and intracoronary imaging using intravascular ultrasound or optical coherence tomography is often required to confirm the diagnosis. The angiographic appearance of Type 2 is often missed and shorter lengths, such as 20-30 mm, may require repeat angiography or intracoronary imaging to make the diagnosis [4, 6]. The patient in this case had a Type 2 SCAD lesion with suggestive features on the initial angiogram that was confirmed with a repeat angiogram showing healing of her lesion. The LAD is the most common artery affected in both pregnancy-associated and non-pregnancy-associated SCAD [2, 3]. Patients with pregnancy-associated SCAD often have more severe clinical presentations than non-pregnancy-related SCAD with multivessel dissections and acute heart failure [3].
Once a diagnosis is made, SCAD consensus guidelines recommend a conservative approach in patients who are hemodynamically stable and without active ischemia [2, 4, 6]. Invasive management in SCAD is associated with a high incidence of iatrogenic coronary dissection. Patients should be initiated on aspirin, beta-blockade, and additional antiplatelet therapy with clopidogrel for up to 12 months after the initial event. The role of antiplatelet therapy in SCAD is unclear but is extrapolated from its evidence in acute coronary syndrome and may be beneficial with prothrombotic intimal tears. Beta-blockade is thought to reduce arterial shear stress and may be beneficial through mechanisms similar to that of the treatment of aortic dissection [6]. The majority of SCAD patients (70-90%) managed conservatively have spontaneous healing of their dissection. However, patients with hemodynamic instability, electrical instability, ongoing/recurrent ischemia, abnormal blood flow (TIMI 0-1), and/or left-main coronary artery dissection should be considered for urgent revascularization [2].
Due to the risk of early dissection recurrence or extension, SCAD patients should be observed inpatient for 2-4 days until asymptomatic and clinically stable [4, 6]. Patients with pregnancy-associated SCAD have been found to have a higher prevalence of multivessel dissection events [3]. The patient had a new dissection event on her repeat coronary angiogram but remained chest-pain free without any new evidence of ischemia. There is growing evidence into the role that pregnancy and future pregnancy play with SCAD recurrence and the rates of recurrence have been reported to be as high as 30 percent [7]. This creates a relevant ethical question, and a recent experience-based survey reported that the majority of responders discourage future pregnancy after SCAD [8]. Patients who decide to proceed with pregnancy should have dedicated care with cardiologists and obstetric specialists [7].
4. Conclusion
SCAD is an important and underdiagnosed cause of MI associated with pregnancy. Clinicians should maintain high suspicion in women presenting with chest pain in the postpartum period. The diagnosis of SCAD should be made with early angiography, and a conservative approach with medical management is recommended if possible. All patients with SCAD should be followed closely outpatient as researchers learn more information on the factors associated with recurrence.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors' Contributions
All authors had a role in writing and reviewing this case report.
Figure 1 Patient's initial ECG showing ST-segment elevation in V2-V5, consistent with anterior STEMI.
Figure 2 Frame A: initial angiogram showing Type 2 SCAD, with a long segment of diffuse vessel narrowing in the mid to distal LAD. Frame B: initial angiogram showing the PDA with no angiographic disease or narrowing. Frame C: repeat angiogram on hospital day 6 showing healing of initial SCAD lesion after medical therapy. Frame D: repeat angiogram showing new Type 2 SCAD lesion in the mid-PDA.
Figure 3 Repeat ECG on day 2 of hospitalization showing the expected evolution of anterior STEMI with QS waves and T-wave inversions seen in V2-V5. | METOPROLOL | DrugsGivenReaction | CC BY | 33510913 | 19,299,657 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperbilirubinaemia neonatal'. | Pregnancy-Associated Chest Pain: A Case of Spontaneous Coronary Artery Dissection.
Spontaneous Coronary Artery Dissection (SCAD) is an important cause of myocardial infarction that typically affects women without traditional cardiovascular risk factors. It is the most common cause of myocardial infarction in pregnant and postpartum women. SCAD is often underdiagnosed due to the lack of clinician familiarity, and patients with pregnancy-associated SCAD often have more severe clinical presentations than those without. We present a case of SCAD in a multiparous woman who presented with acute chest pain in the postpartum period.
1. Introduction
SCAD is a rare but important cause of myocardial infarction (MI) and sudden cardiac death. SCAD is defined as an epicardial coronary dissection not associated with atherosclerosis, trauma, or iatrogenic injury and is the most common cause of pregnancy-associated and postpartum MI [1]. SCAD typically occurs in women without traditional atherosclerotic cardiovascular risk factors, and the mechanism of injury is thought to be coronary artery obstruction from an intramural hematoma or intimal disruption [2]. Risk factors for SCAD are fibromuscular dysplasia, connective tissue disease, physical stress, emotional stress, pregnancy, and multiparity. It is hypothesized that hormonal changes during pregnancy weaken the coronary arterial vessel walls; multiparous women can accumulate these changes over several pregnancies [2].
Patients with pregnancy-associated SCAD often have more acute presentations and high-risk features than patients with non-pregnancy-associated SCAD. Most cases of pregnancy-associated SCAD occur in the first month postpartum, with the majority in the first week following delivery [3]. It is important to recognize SCAD in clinical practice as the population affected, and management is different than other causes of MI.
2. Case Report
A 44-year-old gravida 6 para 4 postpartum woman presented to the emergency department (ED) complaining of substernal chest pain. That afternoon, she experienced sudden-onset severe left-sided chest pain radiating to her back and shoulder. She had been discharged four days prior after induction of labor for chronic hypertension with an uncomplicated vaginal birth. Her medical history was notable only for hypertension, for which she took metoprolol. She was maintained on metoprolol with good blood pressure control for the duration of her pregnancy and after induction. The day prior to admission she was under significant emotional distress after her infant was hospitalized with hyperbilirubinemia.
In the ED, the patient was afebrile, her blood pressure was 164/101 mm Hg, her heart rate was 60 beats per minute, and she was breathing 16 breaths per minute. Her cardiovascular examination was unremarkable with normal heart sounds with no murmurs, rubs, or gallops and no jugular venous distension. Her lungs were clear, her abdomen was soft, and she had no extremity edema. Her complete blood count and comprehensive metabolic panel results were within normal limits. Her initial troponin I was 0.41 ng/mL (reference range, <0.04 ng/mL), and her electrocardiogram (ECG) (Figure 1) was significant for ST elevation in leads V2-V5 consistent with an anterior ST-segment elevation myocardial infarction (STEMI). Her chest X-ray showed normal mediastinum, no signs of cardiomegaly, and clear lungs.
Given the concern for acute coronary syndrome (ACS), the patient was emergently taken to the cardiac catheterization lab. Her coronary angiogram showed haziness of the midleft anterior descending (LAD) artery followed by an abrupt change in arterial caliber extending to the distal LAD and diagonal branches (Figure 2(a)). There was no clear visualization of a dissection flap, but there was a visible long segment of diffuse vessel narrowing in the mid to distal LAD highly suspicious for coronary dissection. Contrast flow in the distal vessel was normal (TIMI 3), and there were no luminal changes with the administration of intracoronary nitroglycerin. There was no angiographic evidence of atherosclerotic disease in any of her coronary arteries, and no evidence of narrowing in the coronary arteries outside of the LAD. Her chest pain was resolved during the procedure, and her ECG showed normalization of her ST elevation. Given the patient's hemodynamic stability, normal blood flow in the distal LAD, resolution of chest pain, and suspicion for dissection, she was managed conservatively.
She was started on IV nitroglycerin for hypertension, metoprolol, and dual antiplatelet therapy with aspirin and clopidogrel and then transferred to the coronary care unit for close observation. Her transthoracic echocardiogram showed normal left ventricular function with an ejection fraction of 68% and hypokinetic septal and apical walls in the distribution of the LAD. Her repeat ECG (Figure 3) showed the expected evolution of her STEMI with QS waves and T-wave inversions seen in leads V2-V5. She was weaned off the nitroglycerin and transitioned to captopril and nifedipine for strict blood pressure control and safety with breastfeeding.
She remained chest-pain free during the course of the hospitalization and underwent a repeat angiogram to evaluate for the progression of disease given the diagnostic uncertainty. Her repeat angiogram on day 6 of hospitalization showed complete resolution of the LAD lesion (Figure 2(c)) consistent with dissection. Compared to the initial angiogram, the area of haziness was no longer present, and the vessel tapered appropriately towards the apical LAD. However, a new tubular narrowing with abrupt vessel caliber change (Figure 2(d)) was noted in the midposterior descending artery (PDA), compared to her initial angiogram (Figure 2(b)) with normal flow and no clear dissection flap. This event was concerning for a new dissection event. The patient was asymptomatic throughout her hospitalization and was discharged home with close obstetric, primary care, and cardiology outpatient follow-up.
3. Discussion
In this postpartum woman presenting with a STEMI with angiographic findings suggestive of coronary dissection and no evidence of atherosclerotic disease, a diagnosis of SCAD was made. SCAD commonly presents as ACS with ST-segment changes, and early angiography should be performed to confirm the diagnosis, assess the coronary anatomy, and facilitate revascularization when necessary [2–4]. SCAD is often misdiagnosed and a research group recently published a flowchart to aid in the diagnosis [5]. Angiographically, SCAD has three main classifications: Type 1 is identified by contrast staining showing multiple lumens, Type 2 is an abrupt change in vessel caliber with diffuse tubular stenoses of varying length, and Type 3 is a focal stenosis that mimics atherosclerosis and intracoronary imaging using intravascular ultrasound or optical coherence tomography is often required to confirm the diagnosis. The angiographic appearance of Type 2 is often missed and shorter lengths, such as 20-30 mm, may require repeat angiography or intracoronary imaging to make the diagnosis [4, 6]. The patient in this case had a Type 2 SCAD lesion with suggestive features on the initial angiogram that was confirmed with a repeat angiogram showing healing of her lesion. The LAD is the most common artery affected in both pregnancy-associated and non-pregnancy-associated SCAD [2, 3]. Patients with pregnancy-associated SCAD often have more severe clinical presentations than non-pregnancy-related SCAD with multivessel dissections and acute heart failure [3].
Once a diagnosis is made, SCAD consensus guidelines recommend a conservative approach in patients who are hemodynamically stable and without active ischemia [2, 4, 6]. Invasive management in SCAD is associated with a high incidence of iatrogenic coronary dissection. Patients should be initiated on aspirin, beta-blockade, and additional antiplatelet therapy with clopidogrel for up to 12 months after the initial event. The role of antiplatelet therapy in SCAD is unclear but is extrapolated from its evidence in acute coronary syndrome and may be beneficial with prothrombotic intimal tears. Beta-blockade is thought to reduce arterial shear stress and may be beneficial through mechanisms similar to that of the treatment of aortic dissection [6]. The majority of SCAD patients (70-90%) managed conservatively have spontaneous healing of their dissection. However, patients with hemodynamic instability, electrical instability, ongoing/recurrent ischemia, abnormal blood flow (TIMI 0-1), and/or left-main coronary artery dissection should be considered for urgent revascularization [2].
Due to the risk of early dissection recurrence or extension, SCAD patients should be observed inpatient for 2-4 days until asymptomatic and clinically stable [4, 6]. Patients with pregnancy-associated SCAD have been found to have a higher prevalence of multivessel dissection events [3]. The patient had a new dissection event on her repeat coronary angiogram but remained chest-pain free without any new evidence of ischemia. There is growing evidence into the role that pregnancy and future pregnancy play with SCAD recurrence and the rates of recurrence have been reported to be as high as 30 percent [7]. This creates a relevant ethical question, and a recent experience-based survey reported that the majority of responders discourage future pregnancy after SCAD [8]. Patients who decide to proceed with pregnancy should have dedicated care with cardiologists and obstetric specialists [7].
4. Conclusion
SCAD is an important and underdiagnosed cause of MI associated with pregnancy. Clinicians should maintain high suspicion in women presenting with chest pain in the postpartum period. The diagnosis of SCAD should be made with early angiography, and a conservative approach with medical management is recommended if possible. All patients with SCAD should be followed closely outpatient as researchers learn more information on the factors associated with recurrence.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors' Contributions
All authors had a role in writing and reviewing this case report.
Figure 1 Patient's initial ECG showing ST-segment elevation in V2-V5, consistent with anterior STEMI.
Figure 2 Frame A: initial angiogram showing Type 2 SCAD, with a long segment of diffuse vessel narrowing in the mid to distal LAD. Frame B: initial angiogram showing the PDA with no angiographic disease or narrowing. Frame C: repeat angiogram on hospital day 6 showing healing of initial SCAD lesion after medical therapy. Frame D: repeat angiogram showing new Type 2 SCAD lesion in the mid-PDA.
Figure 3 Repeat ECG on day 2 of hospitalization showing the expected evolution of anterior STEMI with QS waves and T-wave inversions seen in V2-V5. | METOPROLOL | DrugsGivenReaction | CC BY | 33510913 | 19,299,657 | 2021 |
What was the administration route of drug 'METOPROLOL'? | Pregnancy-Associated Chest Pain: A Case of Spontaneous Coronary Artery Dissection.
Spontaneous Coronary Artery Dissection (SCAD) is an important cause of myocardial infarction that typically affects women without traditional cardiovascular risk factors. It is the most common cause of myocardial infarction in pregnant and postpartum women. SCAD is often underdiagnosed due to the lack of clinician familiarity, and patients with pregnancy-associated SCAD often have more severe clinical presentations than those without. We present a case of SCAD in a multiparous woman who presented with acute chest pain in the postpartum period.
1. Introduction
SCAD is a rare but important cause of myocardial infarction (MI) and sudden cardiac death. SCAD is defined as an epicardial coronary dissection not associated with atherosclerosis, trauma, or iatrogenic injury and is the most common cause of pregnancy-associated and postpartum MI [1]. SCAD typically occurs in women without traditional atherosclerotic cardiovascular risk factors, and the mechanism of injury is thought to be coronary artery obstruction from an intramural hematoma or intimal disruption [2]. Risk factors for SCAD are fibromuscular dysplasia, connective tissue disease, physical stress, emotional stress, pregnancy, and multiparity. It is hypothesized that hormonal changes during pregnancy weaken the coronary arterial vessel walls; multiparous women can accumulate these changes over several pregnancies [2].
Patients with pregnancy-associated SCAD often have more acute presentations and high-risk features than patients with non-pregnancy-associated SCAD. Most cases of pregnancy-associated SCAD occur in the first month postpartum, with the majority in the first week following delivery [3]. It is important to recognize SCAD in clinical practice as the population affected, and management is different than other causes of MI.
2. Case Report
A 44-year-old gravida 6 para 4 postpartum woman presented to the emergency department (ED) complaining of substernal chest pain. That afternoon, she experienced sudden-onset severe left-sided chest pain radiating to her back and shoulder. She had been discharged four days prior after induction of labor for chronic hypertension with an uncomplicated vaginal birth. Her medical history was notable only for hypertension, for which she took metoprolol. She was maintained on metoprolol with good blood pressure control for the duration of her pregnancy and after induction. The day prior to admission she was under significant emotional distress after her infant was hospitalized with hyperbilirubinemia.
In the ED, the patient was afebrile, her blood pressure was 164/101 mm Hg, her heart rate was 60 beats per minute, and she was breathing 16 breaths per minute. Her cardiovascular examination was unremarkable with normal heart sounds with no murmurs, rubs, or gallops and no jugular venous distension. Her lungs were clear, her abdomen was soft, and she had no extremity edema. Her complete blood count and comprehensive metabolic panel results were within normal limits. Her initial troponin I was 0.41 ng/mL (reference range, <0.04 ng/mL), and her electrocardiogram (ECG) (Figure 1) was significant for ST elevation in leads V2-V5 consistent with an anterior ST-segment elevation myocardial infarction (STEMI). Her chest X-ray showed normal mediastinum, no signs of cardiomegaly, and clear lungs.
Given the concern for acute coronary syndrome (ACS), the patient was emergently taken to the cardiac catheterization lab. Her coronary angiogram showed haziness of the midleft anterior descending (LAD) artery followed by an abrupt change in arterial caliber extending to the distal LAD and diagonal branches (Figure 2(a)). There was no clear visualization of a dissection flap, but there was a visible long segment of diffuse vessel narrowing in the mid to distal LAD highly suspicious for coronary dissection. Contrast flow in the distal vessel was normal (TIMI 3), and there were no luminal changes with the administration of intracoronary nitroglycerin. There was no angiographic evidence of atherosclerotic disease in any of her coronary arteries, and no evidence of narrowing in the coronary arteries outside of the LAD. Her chest pain was resolved during the procedure, and her ECG showed normalization of her ST elevation. Given the patient's hemodynamic stability, normal blood flow in the distal LAD, resolution of chest pain, and suspicion for dissection, she was managed conservatively.
She was started on IV nitroglycerin for hypertension, metoprolol, and dual antiplatelet therapy with aspirin and clopidogrel and then transferred to the coronary care unit for close observation. Her transthoracic echocardiogram showed normal left ventricular function with an ejection fraction of 68% and hypokinetic septal and apical walls in the distribution of the LAD. Her repeat ECG (Figure 3) showed the expected evolution of her STEMI with QS waves and T-wave inversions seen in leads V2-V5. She was weaned off the nitroglycerin and transitioned to captopril and nifedipine for strict blood pressure control and safety with breastfeeding.
She remained chest-pain free during the course of the hospitalization and underwent a repeat angiogram to evaluate for the progression of disease given the diagnostic uncertainty. Her repeat angiogram on day 6 of hospitalization showed complete resolution of the LAD lesion (Figure 2(c)) consistent with dissection. Compared to the initial angiogram, the area of haziness was no longer present, and the vessel tapered appropriately towards the apical LAD. However, a new tubular narrowing with abrupt vessel caliber change (Figure 2(d)) was noted in the midposterior descending artery (PDA), compared to her initial angiogram (Figure 2(b)) with normal flow and no clear dissection flap. This event was concerning for a new dissection event. The patient was asymptomatic throughout her hospitalization and was discharged home with close obstetric, primary care, and cardiology outpatient follow-up.
3. Discussion
In this postpartum woman presenting with a STEMI with angiographic findings suggestive of coronary dissection and no evidence of atherosclerotic disease, a diagnosis of SCAD was made. SCAD commonly presents as ACS with ST-segment changes, and early angiography should be performed to confirm the diagnosis, assess the coronary anatomy, and facilitate revascularization when necessary [2–4]. SCAD is often misdiagnosed and a research group recently published a flowchart to aid in the diagnosis [5]. Angiographically, SCAD has three main classifications: Type 1 is identified by contrast staining showing multiple lumens, Type 2 is an abrupt change in vessel caliber with diffuse tubular stenoses of varying length, and Type 3 is a focal stenosis that mimics atherosclerosis and intracoronary imaging using intravascular ultrasound or optical coherence tomography is often required to confirm the diagnosis. The angiographic appearance of Type 2 is often missed and shorter lengths, such as 20-30 mm, may require repeat angiography or intracoronary imaging to make the diagnosis [4, 6]. The patient in this case had a Type 2 SCAD lesion with suggestive features on the initial angiogram that was confirmed with a repeat angiogram showing healing of her lesion. The LAD is the most common artery affected in both pregnancy-associated and non-pregnancy-associated SCAD [2, 3]. Patients with pregnancy-associated SCAD often have more severe clinical presentations than non-pregnancy-related SCAD with multivessel dissections and acute heart failure [3].
Once a diagnosis is made, SCAD consensus guidelines recommend a conservative approach in patients who are hemodynamically stable and without active ischemia [2, 4, 6]. Invasive management in SCAD is associated with a high incidence of iatrogenic coronary dissection. Patients should be initiated on aspirin, beta-blockade, and additional antiplatelet therapy with clopidogrel for up to 12 months after the initial event. The role of antiplatelet therapy in SCAD is unclear but is extrapolated from its evidence in acute coronary syndrome and may be beneficial with prothrombotic intimal tears. Beta-blockade is thought to reduce arterial shear stress and may be beneficial through mechanisms similar to that of the treatment of aortic dissection [6]. The majority of SCAD patients (70-90%) managed conservatively have spontaneous healing of their dissection. However, patients with hemodynamic instability, electrical instability, ongoing/recurrent ischemia, abnormal blood flow (TIMI 0-1), and/or left-main coronary artery dissection should be considered for urgent revascularization [2].
Due to the risk of early dissection recurrence or extension, SCAD patients should be observed inpatient for 2-4 days until asymptomatic and clinically stable [4, 6]. Patients with pregnancy-associated SCAD have been found to have a higher prevalence of multivessel dissection events [3]. The patient had a new dissection event on her repeat coronary angiogram but remained chest-pain free without any new evidence of ischemia. There is growing evidence into the role that pregnancy and future pregnancy play with SCAD recurrence and the rates of recurrence have been reported to be as high as 30 percent [7]. This creates a relevant ethical question, and a recent experience-based survey reported that the majority of responders discourage future pregnancy after SCAD [8]. Patients who decide to proceed with pregnancy should have dedicated care with cardiologists and obstetric specialists [7].
4. Conclusion
SCAD is an important and underdiagnosed cause of MI associated with pregnancy. Clinicians should maintain high suspicion in women presenting with chest pain in the postpartum period. The diagnosis of SCAD should be made with early angiography, and a conservative approach with medical management is recommended if possible. All patients with SCAD should be followed closely outpatient as researchers learn more information on the factors associated with recurrence.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Authors' Contributions
All authors had a role in writing and reviewing this case report.
Figure 1 Patient's initial ECG showing ST-segment elevation in V2-V5, consistent with anterior STEMI.
Figure 2 Frame A: initial angiogram showing Type 2 SCAD, with a long segment of diffuse vessel narrowing in the mid to distal LAD. Frame B: initial angiogram showing the PDA with no angiographic disease or narrowing. Frame C: repeat angiogram on hospital day 6 showing healing of initial SCAD lesion after medical therapy. Frame D: repeat angiogram showing new Type 2 SCAD lesion in the mid-PDA.
Figure 3 Repeat ECG on day 2 of hospitalization showing the expected evolution of anterior STEMI with QS waves and T-wave inversions seen in V2-V5. | Transplacental | DrugAdministrationRoute | CC BY | 33510913 | 19,299,657 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Humerus fracture'. | Transient Hypophosphatemia: A Dangerous Event in Multiple Myeloma.
Patients with malignancies frequently experience multiple electrolyte disturbances. In multiple myeloma, hypercalcemia and hyperphosphatemia are one of the most common metabolic disturbances observed as part of pathogenesis of the disease. However, in rare occasions and during the course of the disease, many patients can develop hypophosphatemia due to multiple factors that affects the phosphate absorption and excretion. We hereby present a 56 y/o woman recently diagnosed with multiple myeloma who developed severe hypophosphatemia during medical treatment. We should note that the following manuscript was presented at the 2019 American Association of Clinical Endocrinologists (AACE) 28th Annual Scientific and Clinical Congress.
1. Introduction
Cancer is the second cause of death in the United States, and multiple myeloma accounts for approximately 1 to 2 percent of all cancers [1]. In such regard, the American Cancer Society estimates that, in 2020, new cases of multiple myeloma will reach 32,270 in the U.S., while deaths could top 12,830 [2]. This disease is characterized by neoplastic proliferation of immunoglobulin-producing plasma cells, and patients may present a variety of signs or symptoms including, without limitation, bone pain, anemia, acute renal failure, high serum proteins, and multiple electrolyte disturbances. Also, in multiple myeloma, hypercalcemia is observed in approximately one-third of patients and could be mediated by parathyroid hormone-related peptide, osteolytic cytokine production, and excess 1,25-dihydroxyvitamin D production [3, 4]. However, in asymptomatic patients, it is important that pseudohypercalcemia associated to paraproteins is excluded; thus, ionized calcium measurement is recommended. On the contrary, hyperphosphatemia is most likely secondary to renal dysfunction. Nonetheless, hypophosphatemia is rare, and there are few reported cases. For instance, Mao and Ong described a case of hypophosphatemia that was due to paraproteins causing assay interference [5]. As you will see in our case, we faced the classic presentation of multiple myeloma with subsequent development of dangerous hypophosphatemia during medical regimen.
2. Case Report
This is the case of a 56-year-old Hispanic woman with a past medical history of arterial hypertension, type 2 diabetes mellitus, and chronic anemia who was transferred from a community medical clinic to our institution for management of symptomatic anemia, severe hypercalcemia, and renal failure. Upon evaluation at our institution, the patient stated that, for the last three months, she had been experiencing fatigue, generalized weakness, back pain, decreased appetite, and unquantified weight loss. Moreover, the day prior to admission, she had an episode of lightheadedness followed by loss of consciousness for which she was taken to the community medical clinic for evaluation. Upon arrival to our institution, her blood pressure was 161/76 mmHg with a heart rate of 78 bpm, respiratory rate of 18 rpm, temperature of 36.5°C, and peripheral oxygen saturation of 99% at room air. The physical examination provided a remarkable perspective for an acutely ill appearance, generalized paleness, and dry oral mucosa. Initial laboratories were also remarkable for normocytic normochromic anemia of 6.5 g/dL (12.0–14.0), albumin-corrected calcium of 13.8 mg/dL (8.8–10.3), and elevated creatinine of 6.7 mg/dL (0.60–1.10) with a glomerular filtration rate of 7 min/mL (>60). 25-Hydroxyvitamin D was within normal limits at 38.1 ng/ml (30.0–100.0), whereas 1,25-dihydroxyvitamin D was low at 8.6 pg/mL (19.9–79.3). Notwithstanding, the patient had normal phosphorus level in 2.50 mg/dL (2.40–4.20) and normal intact parathyroid hormone in 25 pg/mL (11–67) (see Table 1). Finally, radiographic images disclosed multiple skeletal lytic lesions. In light of such clinical presentation, the patient was admitted into the internal medicine ward with ongoing diagnosis of symptomatic anemia, acute renal failure, and moderate hypercalcemia.
During the early course of hospitalization, both nephrology and hematology/oncology services were consulted for further recommendations regarding renal function deterioration with multiple electrolyte disturbances and a high suspicion of multiple myeloma. The patient was initially managed with aggressive intravenous hydration with isotonic saline and systemic dexamethasone, with marked improvement in renal function during the course of the first week. The results from bone marrow biopsy were consistent with high-risk IgG/kappa multiple myeloma, reason why she was started on chemotherapy with cyclophosphamide, bortezomib, and dexamethasone (CyBorD).
At this point, it was remarkable that the patient continued with corrected hypercalcemia of 11 mg/dL (8.8–10.3) and developed hypophosphatemia of 1.7 mg/dL (2.40–4.20). During the second week of hospitalization, the patient suffered a pathological fracture of the right humerus for which a single dose of zoledronic acid was administered. Therefore, based on the evidence of the pathological fracture, the patient was evaluated by radiation-oncology specialists and was treated with external beam radiotherapy (IMRT technique) up to about the total dose of 4000 cGy.
Furthermore, at day 20, endocrinology service was consulted for recommendations regarding persistent hypophosphatemia despite oral and intravenous replacement. Consequently, new laboratory workup was ordered and was remarkable for marked elevation of intact PTH in 711 pg/ml (11–67), 1,25-dihydroxyvitamin D of 123.0 pg/mL (19.9–79.3), normal albumin-corrected calcium of 8.9 mg/dl (8.8–10.3), and fractional excretion of phosphorus in 14% with reference range <5%. The ionized calcium level was low at 1.15 mEq/L (1.17–1.58) (see Table 2) and phosphorus in 1.4 mg/dl (2.40–4.20).
In view of the persistent hypophosphatemia and the new laboratory results, we considered secondary hyperparathyroidism and pseudohypercalcemia as the etiology of hypophosphatemia. The patient was initiated on calcitriol, and as a result, electrolytes normalized. She was discharged from our institution after 30 days of hospitalization, with remarkable laboratories at the moment of discharge for normal renal function with creatinine at 0.96 mg/dL (0.6–1.10), albumin-corrected calcium at 9.9 mg/dL (8.8–10.3), and phosphorus at 4.70 mg/dL (2.40–4.20) (see Table 3). Eventually, the patient was successfully treated with an autologous stem cell transplant with excellent response.
3. Discussion
Patients with malignancies are exposed to experience multiple metabolic abnormalities. These disturbances can be part of the original process of the disease, medical treatment, or complications during the progression of the disease.
Multiple myeloma (MM) is characterized by proliferation of monoclonal plasma cells in the bone marrow, resulting thereby in overproduction of monoclonal paraproteins. The excessive plasma cell production results in extensive skeletal destruction with osteolytic lesions and pathologic fractures. Also, the deposition of paraproteins in kidneys affecting the renal function coupled with the lytic lesions can provoke the most common electrolyte disturbances seen in MM, which are hypercalcemia and hyperphosphatemia.
In our case, the patient was diagnosed with multiple myeloma with a typical presentation of the disease. During the first weeks of hospitalization, albumin-corrected calcium showed elevated values until ionized calcium ordered during the workup for persistent hypophosphatemia demonstrated the opposite. This finding coupled with the fact that the patient did not present symptoms of hypercalcemia favored the diagnosis of pseudohypercalcemia.
There is evidence that multiple myeloma can occasionally cause laboratory artifacts due to paraproteinemia, causing thereby confusion among physicians. For instance, Ashrafi et al. and Caras reported laboratory interference in electrolytes due to high levels of paraproteins [6, 7]. The proposed mechanisms of these findings include binding of calcium to abnormal immunoglobulins interfering with immunologic assays [4].
Initially, the patient presented normal intact parathyroid hormone (PTH), which exponentially increased after management of factitious hypercalcemia in multiple myeloma. In the absence of high ionized calcium, elevated PTH is the equivalent to secondary hyperparathyroidism [8]. The main mechanism that explains the secondary hyperparathyroidism in our patient is the expected response to true hypocalcemia. As part of the dynamic of parathyroid secretion in response to the ongoing hypocalcemia and improvement in the renal function, intact PTH and 1,25-dihydroxyvitamin D increased significantly provoking the dramatic changes in the homeostasis of phosphorus, which was observed in our case.
In addition, the patient developed severe hypophosphatemia with persistent inadequate response to medical replacement. The effects of elevated parathyroid hormone (PTH) decreased the activity of sodium phosphate cotransporters at the proximal and distal renal tubules, causing an increase in phosphate excretion [9, 10]. This mechanism was evident in our patient with elevated fractional excretion of phosphate during the course of medical management. The primary cause of transient hypophosphatemia in our patient was the secondary hyperparathyroidism caused by true low ionized calcium.
Moreover, several medical therapies utilized in multiple myeloma including, without limitation, volume expansion, bisphosphonates, and corticosteroids, are mainly associated to the increase in phosphorus excretion. Consequently, the patient was treated with a single dose of zoledronic acid infusion, which is a bisphosphonic acid that inhibits the resorption and remodeling activity of the bones. The manufacturer prescribing information of zoledronic acid describes the incidence of hypophosphatemia in 973 patients treated for multiple myeloma and bone metastasis of solid tumors. Grade 3 hypophosphatemia (serum phosphate less than 2 mg/dL) was 12%, while grade 4 hypophosphatemia (serum phosphate less than 1 mg/dL) was less than 1%. Thus, although the exact mechanism of zoledronic acid-induced hypophosphatemia is not completely understood, the hypothesized explanations are that the adverse effect of hypocalcemia provokes induced hyperparathyroidism aggravating the phosphate excretion. This could be a possibility in our case. However, we need to point out the fact that the 973 patients had a median duration of exposure for a safety period of 12.8 months with zoledronic acid every 3-4 weeks, whereas in our case, the patient was treated with a single dose of zoledronic acid. As mentioned, the combined treatments for factitious hypercalcemia coupled with the original process and complications of the disease can trigger electrolyte disorders that could be very challenging to treat.
4. Conclusion
In summary, this case report highlights different uncommon electrolyte disorders that can be found in patients with multiple myeloma. Pseudohypercalcemia in the setting of elevated total proteins should always be taken under consideration, particularly when the patient does not exhibit signs and symptoms suggestive of elevated calcium level. In such cases, measurement of ionized calcium should be strongly considered to determine the true extracellular calcium levels. Additionally, the combined treatment for factitious hypercalcemia and renal impairment can trigger secondary hyperparathyroidism aggravating thereby other electrolyte disorders.
Finally, the multiple electrolyte disturbances faced in multiple myeloma and medication side effects can precipitate serious metabolic disorders such as hypophosphatemia seen in our patient. There are different mechanisms including an increase in phosphate excretion and intracellular shifting worsening the phosphate level. For that reason, the physician should be able to differentiate between true and spurious electrolyte imbalance in order to prevent unnecessary interventions that could be detrimental to the patient.
Data Availability
No data were used to support this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Table 1 Laboratories upon admission.
BUN (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Albumin (g/dL) Total protein (g/dL) Magnesium (mg/dL) Phosphorous (mg/dL) Intact PTH (pg/ml) 1,25-Dihydroxyvitamin D (pg/ml) 25-Hydroxyvitamin D (ng/ml)
67.00 7.00 12.40 2.30 11.50 2.06 2.50 25 8.6 38.1
(8–21) (0.6–1.10) (8.8–10.3) (3.7–4.9) (6.2–7.9) (1.8–2.2) (2.4–4.2) (11–67) (19.9–79.3) (30–100)
Table 2 Laboratories at the moment of endocrinology service evaluation.
BUN (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Albumin (g/dL) Total protein (g/dL) Magnesium (mg/dL) Phosphorous (mg/dL) Intact PTH (pg/ml) 1,25-Dihroxyvitamin D (pg/ml) 1,25-Dihydroxyvitamin D (ng/ml) Ionized calcium (mEq/L)
17.0 1.13 7.50 2.20 8.60 1.73 1.40 711 123 31.7 1.15
(8–21) (0.6–1.10) (8.8–10.3) (3.7–4.9) (6.2–7.9) (1.8–2.2) (2.4–4.2) (11–67) (19.9–79.3) (30–100) (1.17–1.58)
Table 3 Laboratories at the moment of discharge.
BUN (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Albumin (g/dL) Total protein (g/dL) Magnesium (mg/dL) Phosphorous (mg/dL)
8.00 0.96 8.50 2.30 7.80 1.52 4.70
(8–21) (0.6–1.10) (8.8–10.3) (3.7–4.9) (6.2–7.9) (1.8–2.2) (2.4–4.2) | BORTEZOMIB, CYCLOPHOSPHAMIDE, DEXAMETHASONE, SODIUM CHLORIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33510918 | 19,414,397 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pathological fracture'. | Transient Hypophosphatemia: A Dangerous Event in Multiple Myeloma.
Patients with malignancies frequently experience multiple electrolyte disturbances. In multiple myeloma, hypercalcemia and hyperphosphatemia are one of the most common metabolic disturbances observed as part of pathogenesis of the disease. However, in rare occasions and during the course of the disease, many patients can develop hypophosphatemia due to multiple factors that affects the phosphate absorption and excretion. We hereby present a 56 y/o woman recently diagnosed with multiple myeloma who developed severe hypophosphatemia during medical treatment. We should note that the following manuscript was presented at the 2019 American Association of Clinical Endocrinologists (AACE) 28th Annual Scientific and Clinical Congress.
1. Introduction
Cancer is the second cause of death in the United States, and multiple myeloma accounts for approximately 1 to 2 percent of all cancers [1]. In such regard, the American Cancer Society estimates that, in 2020, new cases of multiple myeloma will reach 32,270 in the U.S., while deaths could top 12,830 [2]. This disease is characterized by neoplastic proliferation of immunoglobulin-producing plasma cells, and patients may present a variety of signs or symptoms including, without limitation, bone pain, anemia, acute renal failure, high serum proteins, and multiple electrolyte disturbances. Also, in multiple myeloma, hypercalcemia is observed in approximately one-third of patients and could be mediated by parathyroid hormone-related peptide, osteolytic cytokine production, and excess 1,25-dihydroxyvitamin D production [3, 4]. However, in asymptomatic patients, it is important that pseudohypercalcemia associated to paraproteins is excluded; thus, ionized calcium measurement is recommended. On the contrary, hyperphosphatemia is most likely secondary to renal dysfunction. Nonetheless, hypophosphatemia is rare, and there are few reported cases. For instance, Mao and Ong described a case of hypophosphatemia that was due to paraproteins causing assay interference [5]. As you will see in our case, we faced the classic presentation of multiple myeloma with subsequent development of dangerous hypophosphatemia during medical regimen.
2. Case Report
This is the case of a 56-year-old Hispanic woman with a past medical history of arterial hypertension, type 2 diabetes mellitus, and chronic anemia who was transferred from a community medical clinic to our institution for management of symptomatic anemia, severe hypercalcemia, and renal failure. Upon evaluation at our institution, the patient stated that, for the last three months, she had been experiencing fatigue, generalized weakness, back pain, decreased appetite, and unquantified weight loss. Moreover, the day prior to admission, she had an episode of lightheadedness followed by loss of consciousness for which she was taken to the community medical clinic for evaluation. Upon arrival to our institution, her blood pressure was 161/76 mmHg with a heart rate of 78 bpm, respiratory rate of 18 rpm, temperature of 36.5°C, and peripheral oxygen saturation of 99% at room air. The physical examination provided a remarkable perspective for an acutely ill appearance, generalized paleness, and dry oral mucosa. Initial laboratories were also remarkable for normocytic normochromic anemia of 6.5 g/dL (12.0–14.0), albumin-corrected calcium of 13.8 mg/dL (8.8–10.3), and elevated creatinine of 6.7 mg/dL (0.60–1.10) with a glomerular filtration rate of 7 min/mL (>60). 25-Hydroxyvitamin D was within normal limits at 38.1 ng/ml (30.0–100.0), whereas 1,25-dihydroxyvitamin D was low at 8.6 pg/mL (19.9–79.3). Notwithstanding, the patient had normal phosphorus level in 2.50 mg/dL (2.40–4.20) and normal intact parathyroid hormone in 25 pg/mL (11–67) (see Table 1). Finally, radiographic images disclosed multiple skeletal lytic lesions. In light of such clinical presentation, the patient was admitted into the internal medicine ward with ongoing diagnosis of symptomatic anemia, acute renal failure, and moderate hypercalcemia.
During the early course of hospitalization, both nephrology and hematology/oncology services were consulted for further recommendations regarding renal function deterioration with multiple electrolyte disturbances and a high suspicion of multiple myeloma. The patient was initially managed with aggressive intravenous hydration with isotonic saline and systemic dexamethasone, with marked improvement in renal function during the course of the first week. The results from bone marrow biopsy were consistent with high-risk IgG/kappa multiple myeloma, reason why she was started on chemotherapy with cyclophosphamide, bortezomib, and dexamethasone (CyBorD).
At this point, it was remarkable that the patient continued with corrected hypercalcemia of 11 mg/dL (8.8–10.3) and developed hypophosphatemia of 1.7 mg/dL (2.40–4.20). During the second week of hospitalization, the patient suffered a pathological fracture of the right humerus for which a single dose of zoledronic acid was administered. Therefore, based on the evidence of the pathological fracture, the patient was evaluated by radiation-oncology specialists and was treated with external beam radiotherapy (IMRT technique) up to about the total dose of 4000 cGy.
Furthermore, at day 20, endocrinology service was consulted for recommendations regarding persistent hypophosphatemia despite oral and intravenous replacement. Consequently, new laboratory workup was ordered and was remarkable for marked elevation of intact PTH in 711 pg/ml (11–67), 1,25-dihydroxyvitamin D of 123.0 pg/mL (19.9–79.3), normal albumin-corrected calcium of 8.9 mg/dl (8.8–10.3), and fractional excretion of phosphorus in 14% with reference range <5%. The ionized calcium level was low at 1.15 mEq/L (1.17–1.58) (see Table 2) and phosphorus in 1.4 mg/dl (2.40–4.20).
In view of the persistent hypophosphatemia and the new laboratory results, we considered secondary hyperparathyroidism and pseudohypercalcemia as the etiology of hypophosphatemia. The patient was initiated on calcitriol, and as a result, electrolytes normalized. She was discharged from our institution after 30 days of hospitalization, with remarkable laboratories at the moment of discharge for normal renal function with creatinine at 0.96 mg/dL (0.6–1.10), albumin-corrected calcium at 9.9 mg/dL (8.8–10.3), and phosphorus at 4.70 mg/dL (2.40–4.20) (see Table 3). Eventually, the patient was successfully treated with an autologous stem cell transplant with excellent response.
3. Discussion
Patients with malignancies are exposed to experience multiple metabolic abnormalities. These disturbances can be part of the original process of the disease, medical treatment, or complications during the progression of the disease.
Multiple myeloma (MM) is characterized by proliferation of monoclonal plasma cells in the bone marrow, resulting thereby in overproduction of monoclonal paraproteins. The excessive plasma cell production results in extensive skeletal destruction with osteolytic lesions and pathologic fractures. Also, the deposition of paraproteins in kidneys affecting the renal function coupled with the lytic lesions can provoke the most common electrolyte disturbances seen in MM, which are hypercalcemia and hyperphosphatemia.
In our case, the patient was diagnosed with multiple myeloma with a typical presentation of the disease. During the first weeks of hospitalization, albumin-corrected calcium showed elevated values until ionized calcium ordered during the workup for persistent hypophosphatemia demonstrated the opposite. This finding coupled with the fact that the patient did not present symptoms of hypercalcemia favored the diagnosis of pseudohypercalcemia.
There is evidence that multiple myeloma can occasionally cause laboratory artifacts due to paraproteinemia, causing thereby confusion among physicians. For instance, Ashrafi et al. and Caras reported laboratory interference in electrolytes due to high levels of paraproteins [6, 7]. The proposed mechanisms of these findings include binding of calcium to abnormal immunoglobulins interfering with immunologic assays [4].
Initially, the patient presented normal intact parathyroid hormone (PTH), which exponentially increased after management of factitious hypercalcemia in multiple myeloma. In the absence of high ionized calcium, elevated PTH is the equivalent to secondary hyperparathyroidism [8]. The main mechanism that explains the secondary hyperparathyroidism in our patient is the expected response to true hypocalcemia. As part of the dynamic of parathyroid secretion in response to the ongoing hypocalcemia and improvement in the renal function, intact PTH and 1,25-dihydroxyvitamin D increased significantly provoking the dramatic changes in the homeostasis of phosphorus, which was observed in our case.
In addition, the patient developed severe hypophosphatemia with persistent inadequate response to medical replacement. The effects of elevated parathyroid hormone (PTH) decreased the activity of sodium phosphate cotransporters at the proximal and distal renal tubules, causing an increase in phosphate excretion [9, 10]. This mechanism was evident in our patient with elevated fractional excretion of phosphate during the course of medical management. The primary cause of transient hypophosphatemia in our patient was the secondary hyperparathyroidism caused by true low ionized calcium.
Moreover, several medical therapies utilized in multiple myeloma including, without limitation, volume expansion, bisphosphonates, and corticosteroids, are mainly associated to the increase in phosphorus excretion. Consequently, the patient was treated with a single dose of zoledronic acid infusion, which is a bisphosphonic acid that inhibits the resorption and remodeling activity of the bones. The manufacturer prescribing information of zoledronic acid describes the incidence of hypophosphatemia in 973 patients treated for multiple myeloma and bone metastasis of solid tumors. Grade 3 hypophosphatemia (serum phosphate less than 2 mg/dL) was 12%, while grade 4 hypophosphatemia (serum phosphate less than 1 mg/dL) was less than 1%. Thus, although the exact mechanism of zoledronic acid-induced hypophosphatemia is not completely understood, the hypothesized explanations are that the adverse effect of hypocalcemia provokes induced hyperparathyroidism aggravating the phosphate excretion. This could be a possibility in our case. However, we need to point out the fact that the 973 patients had a median duration of exposure for a safety period of 12.8 months with zoledronic acid every 3-4 weeks, whereas in our case, the patient was treated with a single dose of zoledronic acid. As mentioned, the combined treatments for factitious hypercalcemia coupled with the original process and complications of the disease can trigger electrolyte disorders that could be very challenging to treat.
4. Conclusion
In summary, this case report highlights different uncommon electrolyte disorders that can be found in patients with multiple myeloma. Pseudohypercalcemia in the setting of elevated total proteins should always be taken under consideration, particularly when the patient does not exhibit signs and symptoms suggestive of elevated calcium level. In such cases, measurement of ionized calcium should be strongly considered to determine the true extracellular calcium levels. Additionally, the combined treatment for factitious hypercalcemia and renal impairment can trigger secondary hyperparathyroidism aggravating thereby other electrolyte disorders.
Finally, the multiple electrolyte disturbances faced in multiple myeloma and medication side effects can precipitate serious metabolic disorders such as hypophosphatemia seen in our patient. There are different mechanisms including an increase in phosphate excretion and intracellular shifting worsening the phosphate level. For that reason, the physician should be able to differentiate between true and spurious electrolyte imbalance in order to prevent unnecessary interventions that could be detrimental to the patient.
Data Availability
No data were used to support this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Table 1 Laboratories upon admission.
BUN (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Albumin (g/dL) Total protein (g/dL) Magnesium (mg/dL) Phosphorous (mg/dL) Intact PTH (pg/ml) 1,25-Dihydroxyvitamin D (pg/ml) 25-Hydroxyvitamin D (ng/ml)
67.00 7.00 12.40 2.30 11.50 2.06 2.50 25 8.6 38.1
(8–21) (0.6–1.10) (8.8–10.3) (3.7–4.9) (6.2–7.9) (1.8–2.2) (2.4–4.2) (11–67) (19.9–79.3) (30–100)
Table 2 Laboratories at the moment of endocrinology service evaluation.
BUN (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Albumin (g/dL) Total protein (g/dL) Magnesium (mg/dL) Phosphorous (mg/dL) Intact PTH (pg/ml) 1,25-Dihroxyvitamin D (pg/ml) 1,25-Dihydroxyvitamin D (ng/ml) Ionized calcium (mEq/L)
17.0 1.13 7.50 2.20 8.60 1.73 1.40 711 123 31.7 1.15
(8–21) (0.6–1.10) (8.8–10.3) (3.7–4.9) (6.2–7.9) (1.8–2.2) (2.4–4.2) (11–67) (19.9–79.3) (30–100) (1.17–1.58)
Table 3 Laboratories at the moment of discharge.
BUN (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Albumin (g/dL) Total protein (g/dL) Magnesium (mg/dL) Phosphorous (mg/dL)
8.00 0.96 8.50 2.30 7.80 1.52 4.70
(8–21) (0.6–1.10) (8.8–10.3) (3.7–4.9) (6.2–7.9) (1.8–2.2) (2.4–4.2) | BORTEZOMIB, CYCLOPHOSPHAMIDE, DEXAMETHASONE, SODIUM CHLORIDE, ZOLEDRONIC ACID | DrugsGivenReaction | CC BY | 33510918 | 19,401,944 | 2021 |
What was the administration route of drug 'SODIUM CHLORIDE'? | Transient Hypophosphatemia: A Dangerous Event in Multiple Myeloma.
Patients with malignancies frequently experience multiple electrolyte disturbances. In multiple myeloma, hypercalcemia and hyperphosphatemia are one of the most common metabolic disturbances observed as part of pathogenesis of the disease. However, in rare occasions and during the course of the disease, many patients can develop hypophosphatemia due to multiple factors that affects the phosphate absorption and excretion. We hereby present a 56 y/o woman recently diagnosed with multiple myeloma who developed severe hypophosphatemia during medical treatment. We should note that the following manuscript was presented at the 2019 American Association of Clinical Endocrinologists (AACE) 28th Annual Scientific and Clinical Congress.
1. Introduction
Cancer is the second cause of death in the United States, and multiple myeloma accounts for approximately 1 to 2 percent of all cancers [1]. In such regard, the American Cancer Society estimates that, in 2020, new cases of multiple myeloma will reach 32,270 in the U.S., while deaths could top 12,830 [2]. This disease is characterized by neoplastic proliferation of immunoglobulin-producing plasma cells, and patients may present a variety of signs or symptoms including, without limitation, bone pain, anemia, acute renal failure, high serum proteins, and multiple electrolyte disturbances. Also, in multiple myeloma, hypercalcemia is observed in approximately one-third of patients and could be mediated by parathyroid hormone-related peptide, osteolytic cytokine production, and excess 1,25-dihydroxyvitamin D production [3, 4]. However, in asymptomatic patients, it is important that pseudohypercalcemia associated to paraproteins is excluded; thus, ionized calcium measurement is recommended. On the contrary, hyperphosphatemia is most likely secondary to renal dysfunction. Nonetheless, hypophosphatemia is rare, and there are few reported cases. For instance, Mao and Ong described a case of hypophosphatemia that was due to paraproteins causing assay interference [5]. As you will see in our case, we faced the classic presentation of multiple myeloma with subsequent development of dangerous hypophosphatemia during medical regimen.
2. Case Report
This is the case of a 56-year-old Hispanic woman with a past medical history of arterial hypertension, type 2 diabetes mellitus, and chronic anemia who was transferred from a community medical clinic to our institution for management of symptomatic anemia, severe hypercalcemia, and renal failure. Upon evaluation at our institution, the patient stated that, for the last three months, she had been experiencing fatigue, generalized weakness, back pain, decreased appetite, and unquantified weight loss. Moreover, the day prior to admission, she had an episode of lightheadedness followed by loss of consciousness for which she was taken to the community medical clinic for evaluation. Upon arrival to our institution, her blood pressure was 161/76 mmHg with a heart rate of 78 bpm, respiratory rate of 18 rpm, temperature of 36.5°C, and peripheral oxygen saturation of 99% at room air. The physical examination provided a remarkable perspective for an acutely ill appearance, generalized paleness, and dry oral mucosa. Initial laboratories were also remarkable for normocytic normochromic anemia of 6.5 g/dL (12.0–14.0), albumin-corrected calcium of 13.8 mg/dL (8.8–10.3), and elevated creatinine of 6.7 mg/dL (0.60–1.10) with a glomerular filtration rate of 7 min/mL (>60). 25-Hydroxyvitamin D was within normal limits at 38.1 ng/ml (30.0–100.0), whereas 1,25-dihydroxyvitamin D was low at 8.6 pg/mL (19.9–79.3). Notwithstanding, the patient had normal phosphorus level in 2.50 mg/dL (2.40–4.20) and normal intact parathyroid hormone in 25 pg/mL (11–67) (see Table 1). Finally, radiographic images disclosed multiple skeletal lytic lesions. In light of such clinical presentation, the patient was admitted into the internal medicine ward with ongoing diagnosis of symptomatic anemia, acute renal failure, and moderate hypercalcemia.
During the early course of hospitalization, both nephrology and hematology/oncology services were consulted for further recommendations regarding renal function deterioration with multiple electrolyte disturbances and a high suspicion of multiple myeloma. The patient was initially managed with aggressive intravenous hydration with isotonic saline and systemic dexamethasone, with marked improvement in renal function during the course of the first week. The results from bone marrow biopsy were consistent with high-risk IgG/kappa multiple myeloma, reason why she was started on chemotherapy with cyclophosphamide, bortezomib, and dexamethasone (CyBorD).
At this point, it was remarkable that the patient continued with corrected hypercalcemia of 11 mg/dL (8.8–10.3) and developed hypophosphatemia of 1.7 mg/dL (2.40–4.20). During the second week of hospitalization, the patient suffered a pathological fracture of the right humerus for which a single dose of zoledronic acid was administered. Therefore, based on the evidence of the pathological fracture, the patient was evaluated by radiation-oncology specialists and was treated with external beam radiotherapy (IMRT technique) up to about the total dose of 4000 cGy.
Furthermore, at day 20, endocrinology service was consulted for recommendations regarding persistent hypophosphatemia despite oral and intravenous replacement. Consequently, new laboratory workup was ordered and was remarkable for marked elevation of intact PTH in 711 pg/ml (11–67), 1,25-dihydroxyvitamin D of 123.0 pg/mL (19.9–79.3), normal albumin-corrected calcium of 8.9 mg/dl (8.8–10.3), and fractional excretion of phosphorus in 14% with reference range <5%. The ionized calcium level was low at 1.15 mEq/L (1.17–1.58) (see Table 2) and phosphorus in 1.4 mg/dl (2.40–4.20).
In view of the persistent hypophosphatemia and the new laboratory results, we considered secondary hyperparathyroidism and pseudohypercalcemia as the etiology of hypophosphatemia. The patient was initiated on calcitriol, and as a result, electrolytes normalized. She was discharged from our institution after 30 days of hospitalization, with remarkable laboratories at the moment of discharge for normal renal function with creatinine at 0.96 mg/dL (0.6–1.10), albumin-corrected calcium at 9.9 mg/dL (8.8–10.3), and phosphorus at 4.70 mg/dL (2.40–4.20) (see Table 3). Eventually, the patient was successfully treated with an autologous stem cell transplant with excellent response.
3. Discussion
Patients with malignancies are exposed to experience multiple metabolic abnormalities. These disturbances can be part of the original process of the disease, medical treatment, or complications during the progression of the disease.
Multiple myeloma (MM) is characterized by proliferation of monoclonal plasma cells in the bone marrow, resulting thereby in overproduction of monoclonal paraproteins. The excessive plasma cell production results in extensive skeletal destruction with osteolytic lesions and pathologic fractures. Also, the deposition of paraproteins in kidneys affecting the renal function coupled with the lytic lesions can provoke the most common electrolyte disturbances seen in MM, which are hypercalcemia and hyperphosphatemia.
In our case, the patient was diagnosed with multiple myeloma with a typical presentation of the disease. During the first weeks of hospitalization, albumin-corrected calcium showed elevated values until ionized calcium ordered during the workup for persistent hypophosphatemia demonstrated the opposite. This finding coupled with the fact that the patient did not present symptoms of hypercalcemia favored the diagnosis of pseudohypercalcemia.
There is evidence that multiple myeloma can occasionally cause laboratory artifacts due to paraproteinemia, causing thereby confusion among physicians. For instance, Ashrafi et al. and Caras reported laboratory interference in electrolytes due to high levels of paraproteins [6, 7]. The proposed mechanisms of these findings include binding of calcium to abnormal immunoglobulins interfering with immunologic assays [4].
Initially, the patient presented normal intact parathyroid hormone (PTH), which exponentially increased after management of factitious hypercalcemia in multiple myeloma. In the absence of high ionized calcium, elevated PTH is the equivalent to secondary hyperparathyroidism [8]. The main mechanism that explains the secondary hyperparathyroidism in our patient is the expected response to true hypocalcemia. As part of the dynamic of parathyroid secretion in response to the ongoing hypocalcemia and improvement in the renal function, intact PTH and 1,25-dihydroxyvitamin D increased significantly provoking the dramatic changes in the homeostasis of phosphorus, which was observed in our case.
In addition, the patient developed severe hypophosphatemia with persistent inadequate response to medical replacement. The effects of elevated parathyroid hormone (PTH) decreased the activity of sodium phosphate cotransporters at the proximal and distal renal tubules, causing an increase in phosphate excretion [9, 10]. This mechanism was evident in our patient with elevated fractional excretion of phosphate during the course of medical management. The primary cause of transient hypophosphatemia in our patient was the secondary hyperparathyroidism caused by true low ionized calcium.
Moreover, several medical therapies utilized in multiple myeloma including, without limitation, volume expansion, bisphosphonates, and corticosteroids, are mainly associated to the increase in phosphorus excretion. Consequently, the patient was treated with a single dose of zoledronic acid infusion, which is a bisphosphonic acid that inhibits the resorption and remodeling activity of the bones. The manufacturer prescribing information of zoledronic acid describes the incidence of hypophosphatemia in 973 patients treated for multiple myeloma and bone metastasis of solid tumors. Grade 3 hypophosphatemia (serum phosphate less than 2 mg/dL) was 12%, while grade 4 hypophosphatemia (serum phosphate less than 1 mg/dL) was less than 1%. Thus, although the exact mechanism of zoledronic acid-induced hypophosphatemia is not completely understood, the hypothesized explanations are that the adverse effect of hypocalcemia provokes induced hyperparathyroidism aggravating the phosphate excretion. This could be a possibility in our case. However, we need to point out the fact that the 973 patients had a median duration of exposure for a safety period of 12.8 months with zoledronic acid every 3-4 weeks, whereas in our case, the patient was treated with a single dose of zoledronic acid. As mentioned, the combined treatments for factitious hypercalcemia coupled with the original process and complications of the disease can trigger electrolyte disorders that could be very challenging to treat.
4. Conclusion
In summary, this case report highlights different uncommon electrolyte disorders that can be found in patients with multiple myeloma. Pseudohypercalcemia in the setting of elevated total proteins should always be taken under consideration, particularly when the patient does not exhibit signs and symptoms suggestive of elevated calcium level. In such cases, measurement of ionized calcium should be strongly considered to determine the true extracellular calcium levels. Additionally, the combined treatment for factitious hypercalcemia and renal impairment can trigger secondary hyperparathyroidism aggravating thereby other electrolyte disorders.
Finally, the multiple electrolyte disturbances faced in multiple myeloma and medication side effects can precipitate serious metabolic disorders such as hypophosphatemia seen in our patient. There are different mechanisms including an increase in phosphate excretion and intracellular shifting worsening the phosphate level. For that reason, the physician should be able to differentiate between true and spurious electrolyte imbalance in order to prevent unnecessary interventions that could be detrimental to the patient.
Data Availability
No data were used to support this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Table 1 Laboratories upon admission.
BUN (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Albumin (g/dL) Total protein (g/dL) Magnesium (mg/dL) Phosphorous (mg/dL) Intact PTH (pg/ml) 1,25-Dihydroxyvitamin D (pg/ml) 25-Hydroxyvitamin D (ng/ml)
67.00 7.00 12.40 2.30 11.50 2.06 2.50 25 8.6 38.1
(8–21) (0.6–1.10) (8.8–10.3) (3.7–4.9) (6.2–7.9) (1.8–2.2) (2.4–4.2) (11–67) (19.9–79.3) (30–100)
Table 2 Laboratories at the moment of endocrinology service evaluation.
BUN (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Albumin (g/dL) Total protein (g/dL) Magnesium (mg/dL) Phosphorous (mg/dL) Intact PTH (pg/ml) 1,25-Dihroxyvitamin D (pg/ml) 1,25-Dihydroxyvitamin D (ng/ml) Ionized calcium (mEq/L)
17.0 1.13 7.50 2.20 8.60 1.73 1.40 711 123 31.7 1.15
(8–21) (0.6–1.10) (8.8–10.3) (3.7–4.9) (6.2–7.9) (1.8–2.2) (2.4–4.2) (11–67) (19.9–79.3) (30–100) (1.17–1.58)
Table 3 Laboratories at the moment of discharge.
BUN (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Albumin (g/dL) Total protein (g/dL) Magnesium (mg/dL) Phosphorous (mg/dL)
8.00 0.96 8.50 2.30 7.80 1.52 4.70
(8–21) (0.6–1.10) (8.8–10.3) (3.7–4.9) (6.2–7.9) (1.8–2.2) (2.4–4.2) | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33510918 | 19,401,944 | 2021 |
What was the outcome of reaction 'Hypophosphataemia'? | Transient Hypophosphatemia: A Dangerous Event in Multiple Myeloma.
Patients with malignancies frequently experience multiple electrolyte disturbances. In multiple myeloma, hypercalcemia and hyperphosphatemia are one of the most common metabolic disturbances observed as part of pathogenesis of the disease. However, in rare occasions and during the course of the disease, many patients can develop hypophosphatemia due to multiple factors that affects the phosphate absorption and excretion. We hereby present a 56 y/o woman recently diagnosed with multiple myeloma who developed severe hypophosphatemia during medical treatment. We should note that the following manuscript was presented at the 2019 American Association of Clinical Endocrinologists (AACE) 28th Annual Scientific and Clinical Congress.
1. Introduction
Cancer is the second cause of death in the United States, and multiple myeloma accounts for approximately 1 to 2 percent of all cancers [1]. In such regard, the American Cancer Society estimates that, in 2020, new cases of multiple myeloma will reach 32,270 in the U.S., while deaths could top 12,830 [2]. This disease is characterized by neoplastic proliferation of immunoglobulin-producing plasma cells, and patients may present a variety of signs or symptoms including, without limitation, bone pain, anemia, acute renal failure, high serum proteins, and multiple electrolyte disturbances. Also, in multiple myeloma, hypercalcemia is observed in approximately one-third of patients and could be mediated by parathyroid hormone-related peptide, osteolytic cytokine production, and excess 1,25-dihydroxyvitamin D production [3, 4]. However, in asymptomatic patients, it is important that pseudohypercalcemia associated to paraproteins is excluded; thus, ionized calcium measurement is recommended. On the contrary, hyperphosphatemia is most likely secondary to renal dysfunction. Nonetheless, hypophosphatemia is rare, and there are few reported cases. For instance, Mao and Ong described a case of hypophosphatemia that was due to paraproteins causing assay interference [5]. As you will see in our case, we faced the classic presentation of multiple myeloma with subsequent development of dangerous hypophosphatemia during medical regimen.
2. Case Report
This is the case of a 56-year-old Hispanic woman with a past medical history of arterial hypertension, type 2 diabetes mellitus, and chronic anemia who was transferred from a community medical clinic to our institution for management of symptomatic anemia, severe hypercalcemia, and renal failure. Upon evaluation at our institution, the patient stated that, for the last three months, she had been experiencing fatigue, generalized weakness, back pain, decreased appetite, and unquantified weight loss. Moreover, the day prior to admission, she had an episode of lightheadedness followed by loss of consciousness for which she was taken to the community medical clinic for evaluation. Upon arrival to our institution, her blood pressure was 161/76 mmHg with a heart rate of 78 bpm, respiratory rate of 18 rpm, temperature of 36.5°C, and peripheral oxygen saturation of 99% at room air. The physical examination provided a remarkable perspective for an acutely ill appearance, generalized paleness, and dry oral mucosa. Initial laboratories were also remarkable for normocytic normochromic anemia of 6.5 g/dL (12.0–14.0), albumin-corrected calcium of 13.8 mg/dL (8.8–10.3), and elevated creatinine of 6.7 mg/dL (0.60–1.10) with a glomerular filtration rate of 7 min/mL (>60). 25-Hydroxyvitamin D was within normal limits at 38.1 ng/ml (30.0–100.0), whereas 1,25-dihydroxyvitamin D was low at 8.6 pg/mL (19.9–79.3). Notwithstanding, the patient had normal phosphorus level in 2.50 mg/dL (2.40–4.20) and normal intact parathyroid hormone in 25 pg/mL (11–67) (see Table 1). Finally, radiographic images disclosed multiple skeletal lytic lesions. In light of such clinical presentation, the patient was admitted into the internal medicine ward with ongoing diagnosis of symptomatic anemia, acute renal failure, and moderate hypercalcemia.
During the early course of hospitalization, both nephrology and hematology/oncology services were consulted for further recommendations regarding renal function deterioration with multiple electrolyte disturbances and a high suspicion of multiple myeloma. The patient was initially managed with aggressive intravenous hydration with isotonic saline and systemic dexamethasone, with marked improvement in renal function during the course of the first week. The results from bone marrow biopsy were consistent with high-risk IgG/kappa multiple myeloma, reason why she was started on chemotherapy with cyclophosphamide, bortezomib, and dexamethasone (CyBorD).
At this point, it was remarkable that the patient continued with corrected hypercalcemia of 11 mg/dL (8.8–10.3) and developed hypophosphatemia of 1.7 mg/dL (2.40–4.20). During the second week of hospitalization, the patient suffered a pathological fracture of the right humerus for which a single dose of zoledronic acid was administered. Therefore, based on the evidence of the pathological fracture, the patient was evaluated by radiation-oncology specialists and was treated with external beam radiotherapy (IMRT technique) up to about the total dose of 4000 cGy.
Furthermore, at day 20, endocrinology service was consulted for recommendations regarding persistent hypophosphatemia despite oral and intravenous replacement. Consequently, new laboratory workup was ordered and was remarkable for marked elevation of intact PTH in 711 pg/ml (11–67), 1,25-dihydroxyvitamin D of 123.0 pg/mL (19.9–79.3), normal albumin-corrected calcium of 8.9 mg/dl (8.8–10.3), and fractional excretion of phosphorus in 14% with reference range <5%. The ionized calcium level was low at 1.15 mEq/L (1.17–1.58) (see Table 2) and phosphorus in 1.4 mg/dl (2.40–4.20).
In view of the persistent hypophosphatemia and the new laboratory results, we considered secondary hyperparathyroidism and pseudohypercalcemia as the etiology of hypophosphatemia. The patient was initiated on calcitriol, and as a result, electrolytes normalized. She was discharged from our institution after 30 days of hospitalization, with remarkable laboratories at the moment of discharge for normal renal function with creatinine at 0.96 mg/dL (0.6–1.10), albumin-corrected calcium at 9.9 mg/dL (8.8–10.3), and phosphorus at 4.70 mg/dL (2.40–4.20) (see Table 3). Eventually, the patient was successfully treated with an autologous stem cell transplant with excellent response.
3. Discussion
Patients with malignancies are exposed to experience multiple metabolic abnormalities. These disturbances can be part of the original process of the disease, medical treatment, or complications during the progression of the disease.
Multiple myeloma (MM) is characterized by proliferation of monoclonal plasma cells in the bone marrow, resulting thereby in overproduction of monoclonal paraproteins. The excessive plasma cell production results in extensive skeletal destruction with osteolytic lesions and pathologic fractures. Also, the deposition of paraproteins in kidneys affecting the renal function coupled with the lytic lesions can provoke the most common electrolyte disturbances seen in MM, which are hypercalcemia and hyperphosphatemia.
In our case, the patient was diagnosed with multiple myeloma with a typical presentation of the disease. During the first weeks of hospitalization, albumin-corrected calcium showed elevated values until ionized calcium ordered during the workup for persistent hypophosphatemia demonstrated the opposite. This finding coupled with the fact that the patient did not present symptoms of hypercalcemia favored the diagnosis of pseudohypercalcemia.
There is evidence that multiple myeloma can occasionally cause laboratory artifacts due to paraproteinemia, causing thereby confusion among physicians. For instance, Ashrafi et al. and Caras reported laboratory interference in electrolytes due to high levels of paraproteins [6, 7]. The proposed mechanisms of these findings include binding of calcium to abnormal immunoglobulins interfering with immunologic assays [4].
Initially, the patient presented normal intact parathyroid hormone (PTH), which exponentially increased after management of factitious hypercalcemia in multiple myeloma. In the absence of high ionized calcium, elevated PTH is the equivalent to secondary hyperparathyroidism [8]. The main mechanism that explains the secondary hyperparathyroidism in our patient is the expected response to true hypocalcemia. As part of the dynamic of parathyroid secretion in response to the ongoing hypocalcemia and improvement in the renal function, intact PTH and 1,25-dihydroxyvitamin D increased significantly provoking the dramatic changes in the homeostasis of phosphorus, which was observed in our case.
In addition, the patient developed severe hypophosphatemia with persistent inadequate response to medical replacement. The effects of elevated parathyroid hormone (PTH) decreased the activity of sodium phosphate cotransporters at the proximal and distal renal tubules, causing an increase in phosphate excretion [9, 10]. This mechanism was evident in our patient with elevated fractional excretion of phosphate during the course of medical management. The primary cause of transient hypophosphatemia in our patient was the secondary hyperparathyroidism caused by true low ionized calcium.
Moreover, several medical therapies utilized in multiple myeloma including, without limitation, volume expansion, bisphosphonates, and corticosteroids, are mainly associated to the increase in phosphorus excretion. Consequently, the patient was treated with a single dose of zoledronic acid infusion, which is a bisphosphonic acid that inhibits the resorption and remodeling activity of the bones. The manufacturer prescribing information of zoledronic acid describes the incidence of hypophosphatemia in 973 patients treated for multiple myeloma and bone metastasis of solid tumors. Grade 3 hypophosphatemia (serum phosphate less than 2 mg/dL) was 12%, while grade 4 hypophosphatemia (serum phosphate less than 1 mg/dL) was less than 1%. Thus, although the exact mechanism of zoledronic acid-induced hypophosphatemia is not completely understood, the hypothesized explanations are that the adverse effect of hypocalcemia provokes induced hyperparathyroidism aggravating the phosphate excretion. This could be a possibility in our case. However, we need to point out the fact that the 973 patients had a median duration of exposure for a safety period of 12.8 months with zoledronic acid every 3-4 weeks, whereas in our case, the patient was treated with a single dose of zoledronic acid. As mentioned, the combined treatments for factitious hypercalcemia coupled with the original process and complications of the disease can trigger electrolyte disorders that could be very challenging to treat.
4. Conclusion
In summary, this case report highlights different uncommon electrolyte disorders that can be found in patients with multiple myeloma. Pseudohypercalcemia in the setting of elevated total proteins should always be taken under consideration, particularly when the patient does not exhibit signs and symptoms suggestive of elevated calcium level. In such cases, measurement of ionized calcium should be strongly considered to determine the true extracellular calcium levels. Additionally, the combined treatment for factitious hypercalcemia and renal impairment can trigger secondary hyperparathyroidism aggravating thereby other electrolyte disorders.
Finally, the multiple electrolyte disturbances faced in multiple myeloma and medication side effects can precipitate serious metabolic disorders such as hypophosphatemia seen in our patient. There are different mechanisms including an increase in phosphate excretion and intracellular shifting worsening the phosphate level. For that reason, the physician should be able to differentiate between true and spurious electrolyte imbalance in order to prevent unnecessary interventions that could be detrimental to the patient.
Data Availability
No data were used to support this study.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Table 1 Laboratories upon admission.
BUN (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Albumin (g/dL) Total protein (g/dL) Magnesium (mg/dL) Phosphorous (mg/dL) Intact PTH (pg/ml) 1,25-Dihydroxyvitamin D (pg/ml) 25-Hydroxyvitamin D (ng/ml)
67.00 7.00 12.40 2.30 11.50 2.06 2.50 25 8.6 38.1
(8–21) (0.6–1.10) (8.8–10.3) (3.7–4.9) (6.2–7.9) (1.8–2.2) (2.4–4.2) (11–67) (19.9–79.3) (30–100)
Table 2 Laboratories at the moment of endocrinology service evaluation.
BUN (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Albumin (g/dL) Total protein (g/dL) Magnesium (mg/dL) Phosphorous (mg/dL) Intact PTH (pg/ml) 1,25-Dihroxyvitamin D (pg/ml) 1,25-Dihydroxyvitamin D (ng/ml) Ionized calcium (mEq/L)
17.0 1.13 7.50 2.20 8.60 1.73 1.40 711 123 31.7 1.15
(8–21) (0.6–1.10) (8.8–10.3) (3.7–4.9) (6.2–7.9) (1.8–2.2) (2.4–4.2) (11–67) (19.9–79.3) (30–100) (1.17–1.58)
Table 3 Laboratories at the moment of discharge.
BUN (mg/dL) Creatinine (mg/dL) Calcium (mg/dL) Albumin (g/dL) Total protein (g/dL) Magnesium (mg/dL) Phosphorous (mg/dL)
8.00 0.96 8.50 2.30 7.80 1.52 4.70
(8–21) (0.6–1.10) (8.8–10.3) (3.7–4.9) (6.2–7.9) (1.8–2.2) (2.4–4.2) | Recovered | ReactionOutcome | CC BY | 33510918 | 19,401,944 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | Rhabdomyolysis following single administration of pembrolizumab: Is severe immune-reaction a marker for durable treatment response?
•Immune checkpoint inhibitors are approved for all mismatch repair deficient tumors.•Although rare, autoimmune myositis complicating pembrolizumab therapy may be fatal.•In this case, pembrolizumab caused rhabdomyolysis but also a durable response.•Severe autoimmune reaction may be associated with durable treatment response.
1 Background
Mismatch repair deficiency defines Lynch syndrome-associated malignancies and confers susceptibility to immune checkpoint inhibitors (ICIs), such as pembrolizumab. In endometrial cancers, long-term durable responses to immunotherapy have been documented (Chan et al., 2020). Toxicities related to ICIs are frequently of autoimmune etiology including rash, thyroid dysfunction, and gastrointestinal toxicity; however, more severe toxicities have been reported in multiple organ systems (Brooks et al., 2019). In a prior publication, Tomoaia et al. described a case of lethal myocarditis in a patient receiving immunotherapy with nivolumab and ipilimumab, demonstrating the potential for catastrophic adverse effects (Tomoaia et al., 2020).
We also present a rare case of ICI-related myopathy, albeit in a Lynch syndrome patient with synchronous gynecologic malignancies. This patient experienced a durable disease response after one dose, suggesting that severe toxicity might be an indicator of enduring immune modulation and extended disease control.
2 Case Report
Our patient is a 33-year-old, morbidly obese (BMI 55 mg/kg2), nulliparous female with synchronous stage IA FIGO grade 2 endometrioid endometrial adenocarcinoma and stage IVB, HPV negative, moderately differentiated, squamous cell carcinoma of the vagina. Immunohistochemical analysis revealed loss of MSH 6 in both the vaginal and endometrial tumors with hormone receptor positivity in the endometrial mass only.
Imaging demonstrated metastatic disease to the bilateral external iliac lymph nodes, measuring 2.5 cm on the left and 2.6 cm on the right, as well as to a subcutaneous abdominal wall mass measuring 2.6 cm. On physical exam, an 8 cm exophytic mass was seen filling the vagina; biopsy of both the vaginal and abdominal wall masses showed squamous cell carcinoma. Pelvic lymph node biopsy was not performed as it would not have changed management, and it was felt that whichever primary had metastasized as far as the abdominal wall was likely to also be the one involving the pelvic nodes. Furthermore, the nodes were not easily accessible via a radiologic-guided procedure. In order to preserve fertility, a levonorgestrel-releasing intrauterine device was placed for treatment of her endometrial carcinoma, while systemic chemotherapy was started with intravenous (IV) cisplatin 50 mg/m2, paclitaxel 135 mg/m2, and bevacizumab 15 mg/kg given on a 21-day cycle. After three cycles, the vaginal mass had dwindled in size to 3 cm and was subsequently excised. Dilation and curettage was also performed. Neither specimen showed residual malignancy or dysplasia. Given her initial tolerance of chemotherapy and good response, 3 additional cycles of paclitaxel, bevacizumab, and cisplatin were planned. However, cisplatin was dropped for the 6th cycle due to cisplatin toxicity. Positron emission technology (PET) scan showed disappearance of the left inguinal lymph node and decrease of the right inguinal lymph node to 1.8 cm. The abdominal wall mass had similarly decreased in size to 1.2 cm upon completion of cytotoxic chemotherapy.
We started IV pembrolizumab 200 mg after germline analysis confirmed a diagnosis of Lynch syndrome with a pathogenic mutation in MSH 6 (c2150_2153delTGAG). Eleven days after her first infusion, she presented with rapidly progressive proximal muscle weakness rendering her unable to walk. There were no other neurologic deficits including ptosis or diplopia. Blood work subsequently showed creatinine kinase (CK) of 16,280 U/L, strongly suggestive of rhabdomyolysis. Additionally, transaminases were elevated to 421 U/L (aspartate transaminase) and 156 U/L (alanine transaminase) with C-reactive protein elevated to 13.8 mg/L and erythrocyte sediment rate to 38 mm/hr. She was admitted for 11 days for aggressive fluid hydration with normal saline at 230 mL/hr and IV solumedrol 125 mg three times daily for 3 days. Fluids and steroids were tapered as her CK decreased (Fig. 1). Rheumatology and neurology evaluated her for alternative etiologies including infection, hypothyroidism, myasthenia gravis, polymyositis, and Guillain-Barre Syndrome. TSH, electrolytes, and full auto-immune work-up were negative. Thus, she was presumptively diagnosed with common terminology criteria for adverse events grade 3 ICI-induced myositis. She received a 6-week prednisone taper on discharge, at which point CK had decreased to 271 U/L and she had returned to her prior functional status.Fig. 1 Serum creatinine kinase trend (U/L) during admission while undergoing treatment; Peak value 16,280 U/L, Nadir value 51 U/L. Figure shows return to baseline in 9 days from beginning treatment.
PET scan performed one month after hospital discharge demonstrated a partial response. Twenty months following a single pembrolizumab infusion, her exams, pap smears and endometrial biopsies remain normal. Her abdominal wall mass has resolved on the most recent PET (Fig. 2A) and the right pelvic lymph node which remains, now measuring 1 cm, has decreased both in size and metabolic activity (Fig. 2B). She is currently awaiting fertility planning with reproductive endocrinology.Fig. 2 (A) Pre-ICI PET-CT (left) shows metastasis to anterior abdominal wall 1.2 × 1.0 cm with SUV 6.4, with disappearance of this lesion on 20 month post-treatment scan (right); (B) Pre-ICI PET CT shows right external iliac lymph node with prominent hypermetabolism, 1.8 × 2.0 cm with SUV 12.5; 20 month post-treatment (right) shows decrease to 1.0 x 1.1cm with SUV 3.1.
3 Discussion
The above case is the first report describing severe immune-mediated myositis after a single dose of pembrolizumab. Katsuya et al. encountered severe myositis with CK elevated to >27,000 U/L only 10 days after the first infusion; however, this was attributed to nivolumab (Sakai et al., 2017). It is unclear if the same toxicity profiles apply to both nivolumab and pembrolizumab. Ours is also the first case to describe myositis in a patient with gynecologic cancer, as most reports focus on lung cancer or melanoma. It is especially surprising to see such a severe reaction in a young, healthy woman without prior medical conditions.
Interestingly, literature more frequently cites the co-occurrence of ICI-induced myopathies with other immune-mediated toxicity. Myositis is more often described accompanied by myasthenia gravis or cardiomyopathy, leading to respiratory failure (Shirai et al., 2016, Pourhassan et al., 2019). In these instances, myositis often portends poor outcomes (Shirai et al., 2016, Pourhassan et al., 2019). Myositis occurring in isolation, while more atypical, may be less grave.
There have been reports of full recovery, though these are the minority of cases (Min and Hodi, 2014). One case series detailed 6 patients, all with immune-mediated myositis after ICI therapy: 2 died, 3 made complete recoveries, and 1 was able to continue with ICI therapy (Shah et al., 2019). The 4 patients who improved had isolated myositis and did not show symptoms of cardiopulmonary disease.
Lastly, this case describes a potent and durable response to immunotherapy. Most authors describe death or progression of disease following ICI-induced myopathy. Min and colleagues are the only other group we found to describe durable response to immunotherapy following immune toxicity, however that was in the case of melanoma after 5 doses of nivolumab (Min and Hodi, 2014). No such responses have previously been seen in patients with gynecologic cancer or after a single dose of ICI. Liewluck et al. recounted one patient found to have no viable tumor on autopsy after pembrolizumab-induced myositis; however, that patient passed due to side effects, making tumor progression, in this case, clinically irrelevant (Liewluck et al., 2018).
In a review of 576 patients, Weber et all reported an association between immune-related side effects and improved response, noting greatest benefit in patients experiencing 3 or more immune-related toxicities, though with no impact on progression free survival (Weber et al., 2017). Our case supports the correlation between disease response and autoimmune side effects.
This report documents rhabdomyolysis as a rare adverse effect of pembrolizumab. This patient has stable disease, is no longer on any therapy, and is able to pursue fertility options. Such a robust response following one cycle of ICI adds to the evidence that severe toxicity, such as rhabdomyolysis, may be a corollary for excellent response to therapy and may represent sustained tumor-immunity. The repercussions of a reaction such as myositis may, in the long run, be a favorable trade-off if disease is significantly impacted.
Funding support
Ensign Endowment for Gynecologic Cancer Research (K.M.)
CRediT authorship contribution statement
Varun Khetan: Data curation, Writing - original draft. Erin A. Blake: Data curation. Marcia A. Ciccone: Conceptualization, Data curation, Formal analysis. Koji Matsuo: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | BEVACIZUMAB, CISPLATIN, LEVONORGESTREL, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33511262 | 18,969,398 | 2021-02 |
What was the administration route of drug 'BEVACIZUMAB'? | Rhabdomyolysis following single administration of pembrolizumab: Is severe immune-reaction a marker for durable treatment response?
•Immune checkpoint inhibitors are approved for all mismatch repair deficient tumors.•Although rare, autoimmune myositis complicating pembrolizumab therapy may be fatal.•In this case, pembrolizumab caused rhabdomyolysis but also a durable response.•Severe autoimmune reaction may be associated with durable treatment response.
1 Background
Mismatch repair deficiency defines Lynch syndrome-associated malignancies and confers susceptibility to immune checkpoint inhibitors (ICIs), such as pembrolizumab. In endometrial cancers, long-term durable responses to immunotherapy have been documented (Chan et al., 2020). Toxicities related to ICIs are frequently of autoimmune etiology including rash, thyroid dysfunction, and gastrointestinal toxicity; however, more severe toxicities have been reported in multiple organ systems (Brooks et al., 2019). In a prior publication, Tomoaia et al. described a case of lethal myocarditis in a patient receiving immunotherapy with nivolumab and ipilimumab, demonstrating the potential for catastrophic adverse effects (Tomoaia et al., 2020).
We also present a rare case of ICI-related myopathy, albeit in a Lynch syndrome patient with synchronous gynecologic malignancies. This patient experienced a durable disease response after one dose, suggesting that severe toxicity might be an indicator of enduring immune modulation and extended disease control.
2 Case Report
Our patient is a 33-year-old, morbidly obese (BMI 55 mg/kg2), nulliparous female with synchronous stage IA FIGO grade 2 endometrioid endometrial adenocarcinoma and stage IVB, HPV negative, moderately differentiated, squamous cell carcinoma of the vagina. Immunohistochemical analysis revealed loss of MSH 6 in both the vaginal and endometrial tumors with hormone receptor positivity in the endometrial mass only.
Imaging demonstrated metastatic disease to the bilateral external iliac lymph nodes, measuring 2.5 cm on the left and 2.6 cm on the right, as well as to a subcutaneous abdominal wall mass measuring 2.6 cm. On physical exam, an 8 cm exophytic mass was seen filling the vagina; biopsy of both the vaginal and abdominal wall masses showed squamous cell carcinoma. Pelvic lymph node biopsy was not performed as it would not have changed management, and it was felt that whichever primary had metastasized as far as the abdominal wall was likely to also be the one involving the pelvic nodes. Furthermore, the nodes were not easily accessible via a radiologic-guided procedure. In order to preserve fertility, a levonorgestrel-releasing intrauterine device was placed for treatment of her endometrial carcinoma, while systemic chemotherapy was started with intravenous (IV) cisplatin 50 mg/m2, paclitaxel 135 mg/m2, and bevacizumab 15 mg/kg given on a 21-day cycle. After three cycles, the vaginal mass had dwindled in size to 3 cm and was subsequently excised. Dilation and curettage was also performed. Neither specimen showed residual malignancy or dysplasia. Given her initial tolerance of chemotherapy and good response, 3 additional cycles of paclitaxel, bevacizumab, and cisplatin were planned. However, cisplatin was dropped for the 6th cycle due to cisplatin toxicity. Positron emission technology (PET) scan showed disappearance of the left inguinal lymph node and decrease of the right inguinal lymph node to 1.8 cm. The abdominal wall mass had similarly decreased in size to 1.2 cm upon completion of cytotoxic chemotherapy.
We started IV pembrolizumab 200 mg after germline analysis confirmed a diagnosis of Lynch syndrome with a pathogenic mutation in MSH 6 (c2150_2153delTGAG). Eleven days after her first infusion, she presented with rapidly progressive proximal muscle weakness rendering her unable to walk. There were no other neurologic deficits including ptosis or diplopia. Blood work subsequently showed creatinine kinase (CK) of 16,280 U/L, strongly suggestive of rhabdomyolysis. Additionally, transaminases were elevated to 421 U/L (aspartate transaminase) and 156 U/L (alanine transaminase) with C-reactive protein elevated to 13.8 mg/L and erythrocyte sediment rate to 38 mm/hr. She was admitted for 11 days for aggressive fluid hydration with normal saline at 230 mL/hr and IV solumedrol 125 mg three times daily for 3 days. Fluids and steroids were tapered as her CK decreased (Fig. 1). Rheumatology and neurology evaluated her for alternative etiologies including infection, hypothyroidism, myasthenia gravis, polymyositis, and Guillain-Barre Syndrome. TSH, electrolytes, and full auto-immune work-up were negative. Thus, she was presumptively diagnosed with common terminology criteria for adverse events grade 3 ICI-induced myositis. She received a 6-week prednisone taper on discharge, at which point CK had decreased to 271 U/L and she had returned to her prior functional status.Fig. 1 Serum creatinine kinase trend (U/L) during admission while undergoing treatment; Peak value 16,280 U/L, Nadir value 51 U/L. Figure shows return to baseline in 9 days from beginning treatment.
PET scan performed one month after hospital discharge demonstrated a partial response. Twenty months following a single pembrolizumab infusion, her exams, pap smears and endometrial biopsies remain normal. Her abdominal wall mass has resolved on the most recent PET (Fig. 2A) and the right pelvic lymph node which remains, now measuring 1 cm, has decreased both in size and metabolic activity (Fig. 2B). She is currently awaiting fertility planning with reproductive endocrinology.Fig. 2 (A) Pre-ICI PET-CT (left) shows metastasis to anterior abdominal wall 1.2 × 1.0 cm with SUV 6.4, with disappearance of this lesion on 20 month post-treatment scan (right); (B) Pre-ICI PET CT shows right external iliac lymph node with prominent hypermetabolism, 1.8 × 2.0 cm with SUV 12.5; 20 month post-treatment (right) shows decrease to 1.0 x 1.1cm with SUV 3.1.
3 Discussion
The above case is the first report describing severe immune-mediated myositis after a single dose of pembrolizumab. Katsuya et al. encountered severe myositis with CK elevated to >27,000 U/L only 10 days after the first infusion; however, this was attributed to nivolumab (Sakai et al., 2017). It is unclear if the same toxicity profiles apply to both nivolumab and pembrolizumab. Ours is also the first case to describe myositis in a patient with gynecologic cancer, as most reports focus on lung cancer or melanoma. It is especially surprising to see such a severe reaction in a young, healthy woman without prior medical conditions.
Interestingly, literature more frequently cites the co-occurrence of ICI-induced myopathies with other immune-mediated toxicity. Myositis is more often described accompanied by myasthenia gravis or cardiomyopathy, leading to respiratory failure (Shirai et al., 2016, Pourhassan et al., 2019). In these instances, myositis often portends poor outcomes (Shirai et al., 2016, Pourhassan et al., 2019). Myositis occurring in isolation, while more atypical, may be less grave.
There have been reports of full recovery, though these are the minority of cases (Min and Hodi, 2014). One case series detailed 6 patients, all with immune-mediated myositis after ICI therapy: 2 died, 3 made complete recoveries, and 1 was able to continue with ICI therapy (Shah et al., 2019). The 4 patients who improved had isolated myositis and did not show symptoms of cardiopulmonary disease.
Lastly, this case describes a potent and durable response to immunotherapy. Most authors describe death or progression of disease following ICI-induced myopathy. Min and colleagues are the only other group we found to describe durable response to immunotherapy following immune toxicity, however that was in the case of melanoma after 5 doses of nivolumab (Min and Hodi, 2014). No such responses have previously been seen in patients with gynecologic cancer or after a single dose of ICI. Liewluck et al. recounted one patient found to have no viable tumor on autopsy after pembrolizumab-induced myositis; however, that patient passed due to side effects, making tumor progression, in this case, clinically irrelevant (Liewluck et al., 2018).
In a review of 576 patients, Weber et all reported an association between immune-related side effects and improved response, noting greatest benefit in patients experiencing 3 or more immune-related toxicities, though with no impact on progression free survival (Weber et al., 2017). Our case supports the correlation between disease response and autoimmune side effects.
This report documents rhabdomyolysis as a rare adverse effect of pembrolizumab. This patient has stable disease, is no longer on any therapy, and is able to pursue fertility options. Such a robust response following one cycle of ICI adds to the evidence that severe toxicity, such as rhabdomyolysis, may be a corollary for excellent response to therapy and may represent sustained tumor-immunity. The repercussions of a reaction such as myositis may, in the long run, be a favorable trade-off if disease is significantly impacted.
Funding support
Ensign Endowment for Gynecologic Cancer Research (K.M.)
CRediT authorship contribution statement
Varun Khetan: Data curation, Writing - original draft. Erin A. Blake: Data curation. Marcia A. Ciccone: Conceptualization, Data curation, Formal analysis. Koji Matsuo: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33511262 | 18,969,398 | 2021-02 |
What was the administration route of drug 'CISPLATIN'? | Rhabdomyolysis following single administration of pembrolizumab: Is severe immune-reaction a marker for durable treatment response?
•Immune checkpoint inhibitors are approved for all mismatch repair deficient tumors.•Although rare, autoimmune myositis complicating pembrolizumab therapy may be fatal.•In this case, pembrolizumab caused rhabdomyolysis but also a durable response.•Severe autoimmune reaction may be associated with durable treatment response.
1 Background
Mismatch repair deficiency defines Lynch syndrome-associated malignancies and confers susceptibility to immune checkpoint inhibitors (ICIs), such as pembrolizumab. In endometrial cancers, long-term durable responses to immunotherapy have been documented (Chan et al., 2020). Toxicities related to ICIs are frequently of autoimmune etiology including rash, thyroid dysfunction, and gastrointestinal toxicity; however, more severe toxicities have been reported in multiple organ systems (Brooks et al., 2019). In a prior publication, Tomoaia et al. described a case of lethal myocarditis in a patient receiving immunotherapy with nivolumab and ipilimumab, demonstrating the potential for catastrophic adverse effects (Tomoaia et al., 2020).
We also present a rare case of ICI-related myopathy, albeit in a Lynch syndrome patient with synchronous gynecologic malignancies. This patient experienced a durable disease response after one dose, suggesting that severe toxicity might be an indicator of enduring immune modulation and extended disease control.
2 Case Report
Our patient is a 33-year-old, morbidly obese (BMI 55 mg/kg2), nulliparous female with synchronous stage IA FIGO grade 2 endometrioid endometrial adenocarcinoma and stage IVB, HPV negative, moderately differentiated, squamous cell carcinoma of the vagina. Immunohistochemical analysis revealed loss of MSH 6 in both the vaginal and endometrial tumors with hormone receptor positivity in the endometrial mass only.
Imaging demonstrated metastatic disease to the bilateral external iliac lymph nodes, measuring 2.5 cm on the left and 2.6 cm on the right, as well as to a subcutaneous abdominal wall mass measuring 2.6 cm. On physical exam, an 8 cm exophytic mass was seen filling the vagina; biopsy of both the vaginal and abdominal wall masses showed squamous cell carcinoma. Pelvic lymph node biopsy was not performed as it would not have changed management, and it was felt that whichever primary had metastasized as far as the abdominal wall was likely to also be the one involving the pelvic nodes. Furthermore, the nodes were not easily accessible via a radiologic-guided procedure. In order to preserve fertility, a levonorgestrel-releasing intrauterine device was placed for treatment of her endometrial carcinoma, while systemic chemotherapy was started with intravenous (IV) cisplatin 50 mg/m2, paclitaxel 135 mg/m2, and bevacizumab 15 mg/kg given on a 21-day cycle. After three cycles, the vaginal mass had dwindled in size to 3 cm and was subsequently excised. Dilation and curettage was also performed. Neither specimen showed residual malignancy or dysplasia. Given her initial tolerance of chemotherapy and good response, 3 additional cycles of paclitaxel, bevacizumab, and cisplatin were planned. However, cisplatin was dropped for the 6th cycle due to cisplatin toxicity. Positron emission technology (PET) scan showed disappearance of the left inguinal lymph node and decrease of the right inguinal lymph node to 1.8 cm. The abdominal wall mass had similarly decreased in size to 1.2 cm upon completion of cytotoxic chemotherapy.
We started IV pembrolizumab 200 mg after germline analysis confirmed a diagnosis of Lynch syndrome with a pathogenic mutation in MSH 6 (c2150_2153delTGAG). Eleven days after her first infusion, she presented with rapidly progressive proximal muscle weakness rendering her unable to walk. There were no other neurologic deficits including ptosis or diplopia. Blood work subsequently showed creatinine kinase (CK) of 16,280 U/L, strongly suggestive of rhabdomyolysis. Additionally, transaminases were elevated to 421 U/L (aspartate transaminase) and 156 U/L (alanine transaminase) with C-reactive protein elevated to 13.8 mg/L and erythrocyte sediment rate to 38 mm/hr. She was admitted for 11 days for aggressive fluid hydration with normal saline at 230 mL/hr and IV solumedrol 125 mg three times daily for 3 days. Fluids and steroids were tapered as her CK decreased (Fig. 1). Rheumatology and neurology evaluated her for alternative etiologies including infection, hypothyroidism, myasthenia gravis, polymyositis, and Guillain-Barre Syndrome. TSH, electrolytes, and full auto-immune work-up were negative. Thus, she was presumptively diagnosed with common terminology criteria for adverse events grade 3 ICI-induced myositis. She received a 6-week prednisone taper on discharge, at which point CK had decreased to 271 U/L and she had returned to her prior functional status.Fig. 1 Serum creatinine kinase trend (U/L) during admission while undergoing treatment; Peak value 16,280 U/L, Nadir value 51 U/L. Figure shows return to baseline in 9 days from beginning treatment.
PET scan performed one month after hospital discharge demonstrated a partial response. Twenty months following a single pembrolizumab infusion, her exams, pap smears and endometrial biopsies remain normal. Her abdominal wall mass has resolved on the most recent PET (Fig. 2A) and the right pelvic lymph node which remains, now measuring 1 cm, has decreased both in size and metabolic activity (Fig. 2B). She is currently awaiting fertility planning with reproductive endocrinology.Fig. 2 (A) Pre-ICI PET-CT (left) shows metastasis to anterior abdominal wall 1.2 × 1.0 cm with SUV 6.4, with disappearance of this lesion on 20 month post-treatment scan (right); (B) Pre-ICI PET CT shows right external iliac lymph node with prominent hypermetabolism, 1.8 × 2.0 cm with SUV 12.5; 20 month post-treatment (right) shows decrease to 1.0 x 1.1cm with SUV 3.1.
3 Discussion
The above case is the first report describing severe immune-mediated myositis after a single dose of pembrolizumab. Katsuya et al. encountered severe myositis with CK elevated to >27,000 U/L only 10 days after the first infusion; however, this was attributed to nivolumab (Sakai et al., 2017). It is unclear if the same toxicity profiles apply to both nivolumab and pembrolizumab. Ours is also the first case to describe myositis in a patient with gynecologic cancer, as most reports focus on lung cancer or melanoma. It is especially surprising to see such a severe reaction in a young, healthy woman without prior medical conditions.
Interestingly, literature more frequently cites the co-occurrence of ICI-induced myopathies with other immune-mediated toxicity. Myositis is more often described accompanied by myasthenia gravis or cardiomyopathy, leading to respiratory failure (Shirai et al., 2016, Pourhassan et al., 2019). In these instances, myositis often portends poor outcomes (Shirai et al., 2016, Pourhassan et al., 2019). Myositis occurring in isolation, while more atypical, may be less grave.
There have been reports of full recovery, though these are the minority of cases (Min and Hodi, 2014). One case series detailed 6 patients, all with immune-mediated myositis after ICI therapy: 2 died, 3 made complete recoveries, and 1 was able to continue with ICI therapy (Shah et al., 2019). The 4 patients who improved had isolated myositis and did not show symptoms of cardiopulmonary disease.
Lastly, this case describes a potent and durable response to immunotherapy. Most authors describe death or progression of disease following ICI-induced myopathy. Min and colleagues are the only other group we found to describe durable response to immunotherapy following immune toxicity, however that was in the case of melanoma after 5 doses of nivolumab (Min and Hodi, 2014). No such responses have previously been seen in patients with gynecologic cancer or after a single dose of ICI. Liewluck et al. recounted one patient found to have no viable tumor on autopsy after pembrolizumab-induced myositis; however, that patient passed due to side effects, making tumor progression, in this case, clinically irrelevant (Liewluck et al., 2018).
In a review of 576 patients, Weber et all reported an association between immune-related side effects and improved response, noting greatest benefit in patients experiencing 3 or more immune-related toxicities, though with no impact on progression free survival (Weber et al., 2017). Our case supports the correlation between disease response and autoimmune side effects.
This report documents rhabdomyolysis as a rare adverse effect of pembrolizumab. This patient has stable disease, is no longer on any therapy, and is able to pursue fertility options. Such a robust response following one cycle of ICI adds to the evidence that severe toxicity, such as rhabdomyolysis, may be a corollary for excellent response to therapy and may represent sustained tumor-immunity. The repercussions of a reaction such as myositis may, in the long run, be a favorable trade-off if disease is significantly impacted.
Funding support
Ensign Endowment for Gynecologic Cancer Research (K.M.)
CRediT authorship contribution statement
Varun Khetan: Data curation, Writing - original draft. Erin A. Blake: Data curation. Marcia A. Ciccone: Conceptualization, Data curation, Formal analysis. Koji Matsuo: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33511262 | 18,969,398 | 2021-02 |
What was the administration route of drug 'LEVONORGESTREL'? | Rhabdomyolysis following single administration of pembrolizumab: Is severe immune-reaction a marker for durable treatment response?
•Immune checkpoint inhibitors are approved for all mismatch repair deficient tumors.•Although rare, autoimmune myositis complicating pembrolizumab therapy may be fatal.•In this case, pembrolizumab caused rhabdomyolysis but also a durable response.•Severe autoimmune reaction may be associated with durable treatment response.
1 Background
Mismatch repair deficiency defines Lynch syndrome-associated malignancies and confers susceptibility to immune checkpoint inhibitors (ICIs), such as pembrolizumab. In endometrial cancers, long-term durable responses to immunotherapy have been documented (Chan et al., 2020). Toxicities related to ICIs are frequently of autoimmune etiology including rash, thyroid dysfunction, and gastrointestinal toxicity; however, more severe toxicities have been reported in multiple organ systems (Brooks et al., 2019). In a prior publication, Tomoaia et al. described a case of lethal myocarditis in a patient receiving immunotherapy with nivolumab and ipilimumab, demonstrating the potential for catastrophic adverse effects (Tomoaia et al., 2020).
We also present a rare case of ICI-related myopathy, albeit in a Lynch syndrome patient with synchronous gynecologic malignancies. This patient experienced a durable disease response after one dose, suggesting that severe toxicity might be an indicator of enduring immune modulation and extended disease control.
2 Case Report
Our patient is a 33-year-old, morbidly obese (BMI 55 mg/kg2), nulliparous female with synchronous stage IA FIGO grade 2 endometrioid endometrial adenocarcinoma and stage IVB, HPV negative, moderately differentiated, squamous cell carcinoma of the vagina. Immunohistochemical analysis revealed loss of MSH 6 in both the vaginal and endometrial tumors with hormone receptor positivity in the endometrial mass only.
Imaging demonstrated metastatic disease to the bilateral external iliac lymph nodes, measuring 2.5 cm on the left and 2.6 cm on the right, as well as to a subcutaneous abdominal wall mass measuring 2.6 cm. On physical exam, an 8 cm exophytic mass was seen filling the vagina; biopsy of both the vaginal and abdominal wall masses showed squamous cell carcinoma. Pelvic lymph node biopsy was not performed as it would not have changed management, and it was felt that whichever primary had metastasized as far as the abdominal wall was likely to also be the one involving the pelvic nodes. Furthermore, the nodes were not easily accessible via a radiologic-guided procedure. In order to preserve fertility, a levonorgestrel-releasing intrauterine device was placed for treatment of her endometrial carcinoma, while systemic chemotherapy was started with intravenous (IV) cisplatin 50 mg/m2, paclitaxel 135 mg/m2, and bevacizumab 15 mg/kg given on a 21-day cycle. After three cycles, the vaginal mass had dwindled in size to 3 cm and was subsequently excised. Dilation and curettage was also performed. Neither specimen showed residual malignancy or dysplasia. Given her initial tolerance of chemotherapy and good response, 3 additional cycles of paclitaxel, bevacizumab, and cisplatin were planned. However, cisplatin was dropped for the 6th cycle due to cisplatin toxicity. Positron emission technology (PET) scan showed disappearance of the left inguinal lymph node and decrease of the right inguinal lymph node to 1.8 cm. The abdominal wall mass had similarly decreased in size to 1.2 cm upon completion of cytotoxic chemotherapy.
We started IV pembrolizumab 200 mg after germline analysis confirmed a diagnosis of Lynch syndrome with a pathogenic mutation in MSH 6 (c2150_2153delTGAG). Eleven days after her first infusion, she presented with rapidly progressive proximal muscle weakness rendering her unable to walk. There were no other neurologic deficits including ptosis or diplopia. Blood work subsequently showed creatinine kinase (CK) of 16,280 U/L, strongly suggestive of rhabdomyolysis. Additionally, transaminases were elevated to 421 U/L (aspartate transaminase) and 156 U/L (alanine transaminase) with C-reactive protein elevated to 13.8 mg/L and erythrocyte sediment rate to 38 mm/hr. She was admitted for 11 days for aggressive fluid hydration with normal saline at 230 mL/hr and IV solumedrol 125 mg three times daily for 3 days. Fluids and steroids were tapered as her CK decreased (Fig. 1). Rheumatology and neurology evaluated her for alternative etiologies including infection, hypothyroidism, myasthenia gravis, polymyositis, and Guillain-Barre Syndrome. TSH, electrolytes, and full auto-immune work-up were negative. Thus, she was presumptively diagnosed with common terminology criteria for adverse events grade 3 ICI-induced myositis. She received a 6-week prednisone taper on discharge, at which point CK had decreased to 271 U/L and she had returned to her prior functional status.Fig. 1 Serum creatinine kinase trend (U/L) during admission while undergoing treatment; Peak value 16,280 U/L, Nadir value 51 U/L. Figure shows return to baseline in 9 days from beginning treatment.
PET scan performed one month after hospital discharge demonstrated a partial response. Twenty months following a single pembrolizumab infusion, her exams, pap smears and endometrial biopsies remain normal. Her abdominal wall mass has resolved on the most recent PET (Fig. 2A) and the right pelvic lymph node which remains, now measuring 1 cm, has decreased both in size and metabolic activity (Fig. 2B). She is currently awaiting fertility planning with reproductive endocrinology.Fig. 2 (A) Pre-ICI PET-CT (left) shows metastasis to anterior abdominal wall 1.2 × 1.0 cm with SUV 6.4, with disappearance of this lesion on 20 month post-treatment scan (right); (B) Pre-ICI PET CT shows right external iliac lymph node with prominent hypermetabolism, 1.8 × 2.0 cm with SUV 12.5; 20 month post-treatment (right) shows decrease to 1.0 x 1.1cm with SUV 3.1.
3 Discussion
The above case is the first report describing severe immune-mediated myositis after a single dose of pembrolizumab. Katsuya et al. encountered severe myositis with CK elevated to >27,000 U/L only 10 days after the first infusion; however, this was attributed to nivolumab (Sakai et al., 2017). It is unclear if the same toxicity profiles apply to both nivolumab and pembrolizumab. Ours is also the first case to describe myositis in a patient with gynecologic cancer, as most reports focus on lung cancer or melanoma. It is especially surprising to see such a severe reaction in a young, healthy woman without prior medical conditions.
Interestingly, literature more frequently cites the co-occurrence of ICI-induced myopathies with other immune-mediated toxicity. Myositis is more often described accompanied by myasthenia gravis or cardiomyopathy, leading to respiratory failure (Shirai et al., 2016, Pourhassan et al., 2019). In these instances, myositis often portends poor outcomes (Shirai et al., 2016, Pourhassan et al., 2019). Myositis occurring in isolation, while more atypical, may be less grave.
There have been reports of full recovery, though these are the minority of cases (Min and Hodi, 2014). One case series detailed 6 patients, all with immune-mediated myositis after ICI therapy: 2 died, 3 made complete recoveries, and 1 was able to continue with ICI therapy (Shah et al., 2019). The 4 patients who improved had isolated myositis and did not show symptoms of cardiopulmonary disease.
Lastly, this case describes a potent and durable response to immunotherapy. Most authors describe death or progression of disease following ICI-induced myopathy. Min and colleagues are the only other group we found to describe durable response to immunotherapy following immune toxicity, however that was in the case of melanoma after 5 doses of nivolumab (Min and Hodi, 2014). No such responses have previously been seen in patients with gynecologic cancer or after a single dose of ICI. Liewluck et al. recounted one patient found to have no viable tumor on autopsy after pembrolizumab-induced myositis; however, that patient passed due to side effects, making tumor progression, in this case, clinically irrelevant (Liewluck et al., 2018).
In a review of 576 patients, Weber et all reported an association between immune-related side effects and improved response, noting greatest benefit in patients experiencing 3 or more immune-related toxicities, though with no impact on progression free survival (Weber et al., 2017). Our case supports the correlation between disease response and autoimmune side effects.
This report documents rhabdomyolysis as a rare adverse effect of pembrolizumab. This patient has stable disease, is no longer on any therapy, and is able to pursue fertility options. Such a robust response following one cycle of ICI adds to the evidence that severe toxicity, such as rhabdomyolysis, may be a corollary for excellent response to therapy and may represent sustained tumor-immunity. The repercussions of a reaction such as myositis may, in the long run, be a favorable trade-off if disease is significantly impacted.
Funding support
Ensign Endowment for Gynecologic Cancer Research (K.M.)
CRediT authorship contribution statement
Varun Khetan: Data curation, Writing - original draft. Erin A. Blake: Data curation. Marcia A. Ciccone: Conceptualization, Data curation, Formal analysis. Koji Matsuo: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | Intra-uterine | DrugAdministrationRoute | CC BY-NC-ND | 33511262 | 18,969,398 | 2021-02 |
What was the administration route of drug 'PACLITAXEL'? | Rhabdomyolysis following single administration of pembrolizumab: Is severe immune-reaction a marker for durable treatment response?
•Immune checkpoint inhibitors are approved for all mismatch repair deficient tumors.•Although rare, autoimmune myositis complicating pembrolizumab therapy may be fatal.•In this case, pembrolizumab caused rhabdomyolysis but also a durable response.•Severe autoimmune reaction may be associated with durable treatment response.
1 Background
Mismatch repair deficiency defines Lynch syndrome-associated malignancies and confers susceptibility to immune checkpoint inhibitors (ICIs), such as pembrolizumab. In endometrial cancers, long-term durable responses to immunotherapy have been documented (Chan et al., 2020). Toxicities related to ICIs are frequently of autoimmune etiology including rash, thyroid dysfunction, and gastrointestinal toxicity; however, more severe toxicities have been reported in multiple organ systems (Brooks et al., 2019). In a prior publication, Tomoaia et al. described a case of lethal myocarditis in a patient receiving immunotherapy with nivolumab and ipilimumab, demonstrating the potential for catastrophic adverse effects (Tomoaia et al., 2020).
We also present a rare case of ICI-related myopathy, albeit in a Lynch syndrome patient with synchronous gynecologic malignancies. This patient experienced a durable disease response after one dose, suggesting that severe toxicity might be an indicator of enduring immune modulation and extended disease control.
2 Case Report
Our patient is a 33-year-old, morbidly obese (BMI 55 mg/kg2), nulliparous female with synchronous stage IA FIGO grade 2 endometrioid endometrial adenocarcinoma and stage IVB, HPV negative, moderately differentiated, squamous cell carcinoma of the vagina. Immunohistochemical analysis revealed loss of MSH 6 in both the vaginal and endometrial tumors with hormone receptor positivity in the endometrial mass only.
Imaging demonstrated metastatic disease to the bilateral external iliac lymph nodes, measuring 2.5 cm on the left and 2.6 cm on the right, as well as to a subcutaneous abdominal wall mass measuring 2.6 cm. On physical exam, an 8 cm exophytic mass was seen filling the vagina; biopsy of both the vaginal and abdominal wall masses showed squamous cell carcinoma. Pelvic lymph node biopsy was not performed as it would not have changed management, and it was felt that whichever primary had metastasized as far as the abdominal wall was likely to also be the one involving the pelvic nodes. Furthermore, the nodes were not easily accessible via a radiologic-guided procedure. In order to preserve fertility, a levonorgestrel-releasing intrauterine device was placed for treatment of her endometrial carcinoma, while systemic chemotherapy was started with intravenous (IV) cisplatin 50 mg/m2, paclitaxel 135 mg/m2, and bevacizumab 15 mg/kg given on a 21-day cycle. After three cycles, the vaginal mass had dwindled in size to 3 cm and was subsequently excised. Dilation and curettage was also performed. Neither specimen showed residual malignancy or dysplasia. Given her initial tolerance of chemotherapy and good response, 3 additional cycles of paclitaxel, bevacizumab, and cisplatin were planned. However, cisplatin was dropped for the 6th cycle due to cisplatin toxicity. Positron emission technology (PET) scan showed disappearance of the left inguinal lymph node and decrease of the right inguinal lymph node to 1.8 cm. The abdominal wall mass had similarly decreased in size to 1.2 cm upon completion of cytotoxic chemotherapy.
We started IV pembrolizumab 200 mg after germline analysis confirmed a diagnosis of Lynch syndrome with a pathogenic mutation in MSH 6 (c2150_2153delTGAG). Eleven days after her first infusion, she presented with rapidly progressive proximal muscle weakness rendering her unable to walk. There were no other neurologic deficits including ptosis or diplopia. Blood work subsequently showed creatinine kinase (CK) of 16,280 U/L, strongly suggestive of rhabdomyolysis. Additionally, transaminases were elevated to 421 U/L (aspartate transaminase) and 156 U/L (alanine transaminase) with C-reactive protein elevated to 13.8 mg/L and erythrocyte sediment rate to 38 mm/hr. She was admitted for 11 days for aggressive fluid hydration with normal saline at 230 mL/hr and IV solumedrol 125 mg three times daily for 3 days. Fluids and steroids were tapered as her CK decreased (Fig. 1). Rheumatology and neurology evaluated her for alternative etiologies including infection, hypothyroidism, myasthenia gravis, polymyositis, and Guillain-Barre Syndrome. TSH, electrolytes, and full auto-immune work-up were negative. Thus, she was presumptively diagnosed with common terminology criteria for adverse events grade 3 ICI-induced myositis. She received a 6-week prednisone taper on discharge, at which point CK had decreased to 271 U/L and she had returned to her prior functional status.Fig. 1 Serum creatinine kinase trend (U/L) during admission while undergoing treatment; Peak value 16,280 U/L, Nadir value 51 U/L. Figure shows return to baseline in 9 days from beginning treatment.
PET scan performed one month after hospital discharge demonstrated a partial response. Twenty months following a single pembrolizumab infusion, her exams, pap smears and endometrial biopsies remain normal. Her abdominal wall mass has resolved on the most recent PET (Fig. 2A) and the right pelvic lymph node which remains, now measuring 1 cm, has decreased both in size and metabolic activity (Fig. 2B). She is currently awaiting fertility planning with reproductive endocrinology.Fig. 2 (A) Pre-ICI PET-CT (left) shows metastasis to anterior abdominal wall 1.2 × 1.0 cm with SUV 6.4, with disappearance of this lesion on 20 month post-treatment scan (right); (B) Pre-ICI PET CT shows right external iliac lymph node with prominent hypermetabolism, 1.8 × 2.0 cm with SUV 12.5; 20 month post-treatment (right) shows decrease to 1.0 x 1.1cm with SUV 3.1.
3 Discussion
The above case is the first report describing severe immune-mediated myositis after a single dose of pembrolizumab. Katsuya et al. encountered severe myositis with CK elevated to >27,000 U/L only 10 days after the first infusion; however, this was attributed to nivolumab (Sakai et al., 2017). It is unclear if the same toxicity profiles apply to both nivolumab and pembrolizumab. Ours is also the first case to describe myositis in a patient with gynecologic cancer, as most reports focus on lung cancer or melanoma. It is especially surprising to see such a severe reaction in a young, healthy woman without prior medical conditions.
Interestingly, literature more frequently cites the co-occurrence of ICI-induced myopathies with other immune-mediated toxicity. Myositis is more often described accompanied by myasthenia gravis or cardiomyopathy, leading to respiratory failure (Shirai et al., 2016, Pourhassan et al., 2019). In these instances, myositis often portends poor outcomes (Shirai et al., 2016, Pourhassan et al., 2019). Myositis occurring in isolation, while more atypical, may be less grave.
There have been reports of full recovery, though these are the minority of cases (Min and Hodi, 2014). One case series detailed 6 patients, all with immune-mediated myositis after ICI therapy: 2 died, 3 made complete recoveries, and 1 was able to continue with ICI therapy (Shah et al., 2019). The 4 patients who improved had isolated myositis and did not show symptoms of cardiopulmonary disease.
Lastly, this case describes a potent and durable response to immunotherapy. Most authors describe death or progression of disease following ICI-induced myopathy. Min and colleagues are the only other group we found to describe durable response to immunotherapy following immune toxicity, however that was in the case of melanoma after 5 doses of nivolumab (Min and Hodi, 2014). No such responses have previously been seen in patients with gynecologic cancer or after a single dose of ICI. Liewluck et al. recounted one patient found to have no viable tumor on autopsy after pembrolizumab-induced myositis; however, that patient passed due to side effects, making tumor progression, in this case, clinically irrelevant (Liewluck et al., 2018).
In a review of 576 patients, Weber et all reported an association between immune-related side effects and improved response, noting greatest benefit in patients experiencing 3 or more immune-related toxicities, though with no impact on progression free survival (Weber et al., 2017). Our case supports the correlation between disease response and autoimmune side effects.
This report documents rhabdomyolysis as a rare adverse effect of pembrolizumab. This patient has stable disease, is no longer on any therapy, and is able to pursue fertility options. Such a robust response following one cycle of ICI adds to the evidence that severe toxicity, such as rhabdomyolysis, may be a corollary for excellent response to therapy and may represent sustained tumor-immunity. The repercussions of a reaction such as myositis may, in the long run, be a favorable trade-off if disease is significantly impacted.
Funding support
Ensign Endowment for Gynecologic Cancer Research (K.M.)
CRediT authorship contribution statement
Varun Khetan: Data curation, Writing - original draft. Erin A. Blake: Data curation. Marcia A. Ciccone: Conceptualization, Data curation, Formal analysis. Koji Matsuo: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33511262 | 18,969,398 | 2021-02 |
What was the dosage of drug 'BEVACIZUMAB'? | Rhabdomyolysis following single administration of pembrolizumab: Is severe immune-reaction a marker for durable treatment response?
•Immune checkpoint inhibitors are approved for all mismatch repair deficient tumors.•Although rare, autoimmune myositis complicating pembrolizumab therapy may be fatal.•In this case, pembrolizumab caused rhabdomyolysis but also a durable response.•Severe autoimmune reaction may be associated with durable treatment response.
1 Background
Mismatch repair deficiency defines Lynch syndrome-associated malignancies and confers susceptibility to immune checkpoint inhibitors (ICIs), such as pembrolizumab. In endometrial cancers, long-term durable responses to immunotherapy have been documented (Chan et al., 2020). Toxicities related to ICIs are frequently of autoimmune etiology including rash, thyroid dysfunction, and gastrointestinal toxicity; however, more severe toxicities have been reported in multiple organ systems (Brooks et al., 2019). In a prior publication, Tomoaia et al. described a case of lethal myocarditis in a patient receiving immunotherapy with nivolumab and ipilimumab, demonstrating the potential for catastrophic adverse effects (Tomoaia et al., 2020).
We also present a rare case of ICI-related myopathy, albeit in a Lynch syndrome patient with synchronous gynecologic malignancies. This patient experienced a durable disease response after one dose, suggesting that severe toxicity might be an indicator of enduring immune modulation and extended disease control.
2 Case Report
Our patient is a 33-year-old, morbidly obese (BMI 55 mg/kg2), nulliparous female with synchronous stage IA FIGO grade 2 endometrioid endometrial adenocarcinoma and stage IVB, HPV negative, moderately differentiated, squamous cell carcinoma of the vagina. Immunohistochemical analysis revealed loss of MSH 6 in both the vaginal and endometrial tumors with hormone receptor positivity in the endometrial mass only.
Imaging demonstrated metastatic disease to the bilateral external iliac lymph nodes, measuring 2.5 cm on the left and 2.6 cm on the right, as well as to a subcutaneous abdominal wall mass measuring 2.6 cm. On physical exam, an 8 cm exophytic mass was seen filling the vagina; biopsy of both the vaginal and abdominal wall masses showed squamous cell carcinoma. Pelvic lymph node biopsy was not performed as it would not have changed management, and it was felt that whichever primary had metastasized as far as the abdominal wall was likely to also be the one involving the pelvic nodes. Furthermore, the nodes were not easily accessible via a radiologic-guided procedure. In order to preserve fertility, a levonorgestrel-releasing intrauterine device was placed for treatment of her endometrial carcinoma, while systemic chemotherapy was started with intravenous (IV) cisplatin 50 mg/m2, paclitaxel 135 mg/m2, and bevacizumab 15 mg/kg given on a 21-day cycle. After three cycles, the vaginal mass had dwindled in size to 3 cm and was subsequently excised. Dilation and curettage was also performed. Neither specimen showed residual malignancy or dysplasia. Given her initial tolerance of chemotherapy and good response, 3 additional cycles of paclitaxel, bevacizumab, and cisplatin were planned. However, cisplatin was dropped for the 6th cycle due to cisplatin toxicity. Positron emission technology (PET) scan showed disappearance of the left inguinal lymph node and decrease of the right inguinal lymph node to 1.8 cm. The abdominal wall mass had similarly decreased in size to 1.2 cm upon completion of cytotoxic chemotherapy.
We started IV pembrolizumab 200 mg after germline analysis confirmed a diagnosis of Lynch syndrome with a pathogenic mutation in MSH 6 (c2150_2153delTGAG). Eleven days after her first infusion, she presented with rapidly progressive proximal muscle weakness rendering her unable to walk. There were no other neurologic deficits including ptosis or diplopia. Blood work subsequently showed creatinine kinase (CK) of 16,280 U/L, strongly suggestive of rhabdomyolysis. Additionally, transaminases were elevated to 421 U/L (aspartate transaminase) and 156 U/L (alanine transaminase) with C-reactive protein elevated to 13.8 mg/L and erythrocyte sediment rate to 38 mm/hr. She was admitted for 11 days for aggressive fluid hydration with normal saline at 230 mL/hr and IV solumedrol 125 mg three times daily for 3 days. Fluids and steroids were tapered as her CK decreased (Fig. 1). Rheumatology and neurology evaluated her for alternative etiologies including infection, hypothyroidism, myasthenia gravis, polymyositis, and Guillain-Barre Syndrome. TSH, electrolytes, and full auto-immune work-up were negative. Thus, she was presumptively diagnosed with common terminology criteria for adverse events grade 3 ICI-induced myositis. She received a 6-week prednisone taper on discharge, at which point CK had decreased to 271 U/L and she had returned to her prior functional status.Fig. 1 Serum creatinine kinase trend (U/L) during admission while undergoing treatment; Peak value 16,280 U/L, Nadir value 51 U/L. Figure shows return to baseline in 9 days from beginning treatment.
PET scan performed one month after hospital discharge demonstrated a partial response. Twenty months following a single pembrolizumab infusion, her exams, pap smears and endometrial biopsies remain normal. Her abdominal wall mass has resolved on the most recent PET (Fig. 2A) and the right pelvic lymph node which remains, now measuring 1 cm, has decreased both in size and metabolic activity (Fig. 2B). She is currently awaiting fertility planning with reproductive endocrinology.Fig. 2 (A) Pre-ICI PET-CT (left) shows metastasis to anterior abdominal wall 1.2 × 1.0 cm with SUV 6.4, with disappearance of this lesion on 20 month post-treatment scan (right); (B) Pre-ICI PET CT shows right external iliac lymph node with prominent hypermetabolism, 1.8 × 2.0 cm with SUV 12.5; 20 month post-treatment (right) shows decrease to 1.0 x 1.1cm with SUV 3.1.
3 Discussion
The above case is the first report describing severe immune-mediated myositis after a single dose of pembrolizumab. Katsuya et al. encountered severe myositis with CK elevated to >27,000 U/L only 10 days after the first infusion; however, this was attributed to nivolumab (Sakai et al., 2017). It is unclear if the same toxicity profiles apply to both nivolumab and pembrolizumab. Ours is also the first case to describe myositis in a patient with gynecologic cancer, as most reports focus on lung cancer or melanoma. It is especially surprising to see such a severe reaction in a young, healthy woman without prior medical conditions.
Interestingly, literature more frequently cites the co-occurrence of ICI-induced myopathies with other immune-mediated toxicity. Myositis is more often described accompanied by myasthenia gravis or cardiomyopathy, leading to respiratory failure (Shirai et al., 2016, Pourhassan et al., 2019). In these instances, myositis often portends poor outcomes (Shirai et al., 2016, Pourhassan et al., 2019). Myositis occurring in isolation, while more atypical, may be less grave.
There have been reports of full recovery, though these are the minority of cases (Min and Hodi, 2014). One case series detailed 6 patients, all with immune-mediated myositis after ICI therapy: 2 died, 3 made complete recoveries, and 1 was able to continue with ICI therapy (Shah et al., 2019). The 4 patients who improved had isolated myositis and did not show symptoms of cardiopulmonary disease.
Lastly, this case describes a potent and durable response to immunotherapy. Most authors describe death or progression of disease following ICI-induced myopathy. Min and colleagues are the only other group we found to describe durable response to immunotherapy following immune toxicity, however that was in the case of melanoma after 5 doses of nivolumab (Min and Hodi, 2014). No such responses have previously been seen in patients with gynecologic cancer or after a single dose of ICI. Liewluck et al. recounted one patient found to have no viable tumor on autopsy after pembrolizumab-induced myositis; however, that patient passed due to side effects, making tumor progression, in this case, clinically irrelevant (Liewluck et al., 2018).
In a review of 576 patients, Weber et all reported an association between immune-related side effects and improved response, noting greatest benefit in patients experiencing 3 or more immune-related toxicities, though with no impact on progression free survival (Weber et al., 2017). Our case supports the correlation between disease response and autoimmune side effects.
This report documents rhabdomyolysis as a rare adverse effect of pembrolizumab. This patient has stable disease, is no longer on any therapy, and is able to pursue fertility options. Such a robust response following one cycle of ICI adds to the evidence that severe toxicity, such as rhabdomyolysis, may be a corollary for excellent response to therapy and may represent sustained tumor-immunity. The repercussions of a reaction such as myositis may, in the long run, be a favorable trade-off if disease is significantly impacted.
Funding support
Ensign Endowment for Gynecologic Cancer Research (K.M.)
CRediT authorship contribution statement
Varun Khetan: Data curation, Writing - original draft. Erin A. Blake: Data curation. Marcia A. Ciccone: Conceptualization, Data curation, Formal analysis. Koji Matsuo: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | 21?DAY CYCLE | DrugDosageText | CC BY-NC-ND | 33511262 | 18,969,398 | 2021-02 |
What was the dosage of drug 'CISPLATIN'? | Rhabdomyolysis following single administration of pembrolizumab: Is severe immune-reaction a marker for durable treatment response?
•Immune checkpoint inhibitors are approved for all mismatch repair deficient tumors.•Although rare, autoimmune myositis complicating pembrolizumab therapy may be fatal.•In this case, pembrolizumab caused rhabdomyolysis but also a durable response.•Severe autoimmune reaction may be associated with durable treatment response.
1 Background
Mismatch repair deficiency defines Lynch syndrome-associated malignancies and confers susceptibility to immune checkpoint inhibitors (ICIs), such as pembrolizumab. In endometrial cancers, long-term durable responses to immunotherapy have been documented (Chan et al., 2020). Toxicities related to ICIs are frequently of autoimmune etiology including rash, thyroid dysfunction, and gastrointestinal toxicity; however, more severe toxicities have been reported in multiple organ systems (Brooks et al., 2019). In a prior publication, Tomoaia et al. described a case of lethal myocarditis in a patient receiving immunotherapy with nivolumab and ipilimumab, demonstrating the potential for catastrophic adverse effects (Tomoaia et al., 2020).
We also present a rare case of ICI-related myopathy, albeit in a Lynch syndrome patient with synchronous gynecologic malignancies. This patient experienced a durable disease response after one dose, suggesting that severe toxicity might be an indicator of enduring immune modulation and extended disease control.
2 Case Report
Our patient is a 33-year-old, morbidly obese (BMI 55 mg/kg2), nulliparous female with synchronous stage IA FIGO grade 2 endometrioid endometrial adenocarcinoma and stage IVB, HPV negative, moderately differentiated, squamous cell carcinoma of the vagina. Immunohistochemical analysis revealed loss of MSH 6 in both the vaginal and endometrial tumors with hormone receptor positivity in the endometrial mass only.
Imaging demonstrated metastatic disease to the bilateral external iliac lymph nodes, measuring 2.5 cm on the left and 2.6 cm on the right, as well as to a subcutaneous abdominal wall mass measuring 2.6 cm. On physical exam, an 8 cm exophytic mass was seen filling the vagina; biopsy of both the vaginal and abdominal wall masses showed squamous cell carcinoma. Pelvic lymph node biopsy was not performed as it would not have changed management, and it was felt that whichever primary had metastasized as far as the abdominal wall was likely to also be the one involving the pelvic nodes. Furthermore, the nodes were not easily accessible via a radiologic-guided procedure. In order to preserve fertility, a levonorgestrel-releasing intrauterine device was placed for treatment of her endometrial carcinoma, while systemic chemotherapy was started with intravenous (IV) cisplatin 50 mg/m2, paclitaxel 135 mg/m2, and bevacizumab 15 mg/kg given on a 21-day cycle. After three cycles, the vaginal mass had dwindled in size to 3 cm and was subsequently excised. Dilation and curettage was also performed. Neither specimen showed residual malignancy or dysplasia. Given her initial tolerance of chemotherapy and good response, 3 additional cycles of paclitaxel, bevacizumab, and cisplatin were planned. However, cisplatin was dropped for the 6th cycle due to cisplatin toxicity. Positron emission technology (PET) scan showed disappearance of the left inguinal lymph node and decrease of the right inguinal lymph node to 1.8 cm. The abdominal wall mass had similarly decreased in size to 1.2 cm upon completion of cytotoxic chemotherapy.
We started IV pembrolizumab 200 mg after germline analysis confirmed a diagnosis of Lynch syndrome with a pathogenic mutation in MSH 6 (c2150_2153delTGAG). Eleven days after her first infusion, she presented with rapidly progressive proximal muscle weakness rendering her unable to walk. There were no other neurologic deficits including ptosis or diplopia. Blood work subsequently showed creatinine kinase (CK) of 16,280 U/L, strongly suggestive of rhabdomyolysis. Additionally, transaminases were elevated to 421 U/L (aspartate transaminase) and 156 U/L (alanine transaminase) with C-reactive protein elevated to 13.8 mg/L and erythrocyte sediment rate to 38 mm/hr. She was admitted for 11 days for aggressive fluid hydration with normal saline at 230 mL/hr and IV solumedrol 125 mg three times daily for 3 days. Fluids and steroids were tapered as her CK decreased (Fig. 1). Rheumatology and neurology evaluated her for alternative etiologies including infection, hypothyroidism, myasthenia gravis, polymyositis, and Guillain-Barre Syndrome. TSH, electrolytes, and full auto-immune work-up were negative. Thus, she was presumptively diagnosed with common terminology criteria for adverse events grade 3 ICI-induced myositis. She received a 6-week prednisone taper on discharge, at which point CK had decreased to 271 U/L and she had returned to her prior functional status.Fig. 1 Serum creatinine kinase trend (U/L) during admission while undergoing treatment; Peak value 16,280 U/L, Nadir value 51 U/L. Figure shows return to baseline in 9 days from beginning treatment.
PET scan performed one month after hospital discharge demonstrated a partial response. Twenty months following a single pembrolizumab infusion, her exams, pap smears and endometrial biopsies remain normal. Her abdominal wall mass has resolved on the most recent PET (Fig. 2A) and the right pelvic lymph node which remains, now measuring 1 cm, has decreased both in size and metabolic activity (Fig. 2B). She is currently awaiting fertility planning with reproductive endocrinology.Fig. 2 (A) Pre-ICI PET-CT (left) shows metastasis to anterior abdominal wall 1.2 × 1.0 cm with SUV 6.4, with disappearance of this lesion on 20 month post-treatment scan (right); (B) Pre-ICI PET CT shows right external iliac lymph node with prominent hypermetabolism, 1.8 × 2.0 cm with SUV 12.5; 20 month post-treatment (right) shows decrease to 1.0 x 1.1cm with SUV 3.1.
3 Discussion
The above case is the first report describing severe immune-mediated myositis after a single dose of pembrolizumab. Katsuya et al. encountered severe myositis with CK elevated to >27,000 U/L only 10 days after the first infusion; however, this was attributed to nivolumab (Sakai et al., 2017). It is unclear if the same toxicity profiles apply to both nivolumab and pembrolizumab. Ours is also the first case to describe myositis in a patient with gynecologic cancer, as most reports focus on lung cancer or melanoma. It is especially surprising to see such a severe reaction in a young, healthy woman without prior medical conditions.
Interestingly, literature more frequently cites the co-occurrence of ICI-induced myopathies with other immune-mediated toxicity. Myositis is more often described accompanied by myasthenia gravis or cardiomyopathy, leading to respiratory failure (Shirai et al., 2016, Pourhassan et al., 2019). In these instances, myositis often portends poor outcomes (Shirai et al., 2016, Pourhassan et al., 2019). Myositis occurring in isolation, while more atypical, may be less grave.
There have been reports of full recovery, though these are the minority of cases (Min and Hodi, 2014). One case series detailed 6 patients, all with immune-mediated myositis after ICI therapy: 2 died, 3 made complete recoveries, and 1 was able to continue with ICI therapy (Shah et al., 2019). The 4 patients who improved had isolated myositis and did not show symptoms of cardiopulmonary disease.
Lastly, this case describes a potent and durable response to immunotherapy. Most authors describe death or progression of disease following ICI-induced myopathy. Min and colleagues are the only other group we found to describe durable response to immunotherapy following immune toxicity, however that was in the case of melanoma after 5 doses of nivolumab (Min and Hodi, 2014). No such responses have previously been seen in patients with gynecologic cancer or after a single dose of ICI. Liewluck et al. recounted one patient found to have no viable tumor on autopsy after pembrolizumab-induced myositis; however, that patient passed due to side effects, making tumor progression, in this case, clinically irrelevant (Liewluck et al., 2018).
In a review of 576 patients, Weber et all reported an association between immune-related side effects and improved response, noting greatest benefit in patients experiencing 3 or more immune-related toxicities, though with no impact on progression free survival (Weber et al., 2017). Our case supports the correlation between disease response and autoimmune side effects.
This report documents rhabdomyolysis as a rare adverse effect of pembrolizumab. This patient has stable disease, is no longer on any therapy, and is able to pursue fertility options. Such a robust response following one cycle of ICI adds to the evidence that severe toxicity, such as rhabdomyolysis, may be a corollary for excellent response to therapy and may represent sustained tumor-immunity. The repercussions of a reaction such as myositis may, in the long run, be a favorable trade-off if disease is significantly impacted.
Funding support
Ensign Endowment for Gynecologic Cancer Research (K.M.)
CRediT authorship contribution statement
Varun Khetan: Data curation, Writing - original draft. Erin A. Blake: Data curation. Marcia A. Ciccone: Conceptualization, Data curation, Formal analysis. Koji Matsuo: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | 21?DAY CYCLE | DrugDosageText | CC BY-NC-ND | 33511262 | 18,969,398 | 2021-02 |
What was the dosage of drug 'LEVONORGESTREL'? | Rhabdomyolysis following single administration of pembrolizumab: Is severe immune-reaction a marker for durable treatment response?
•Immune checkpoint inhibitors are approved for all mismatch repair deficient tumors.•Although rare, autoimmune myositis complicating pembrolizumab therapy may be fatal.•In this case, pembrolizumab caused rhabdomyolysis but also a durable response.•Severe autoimmune reaction may be associated with durable treatment response.
1 Background
Mismatch repair deficiency defines Lynch syndrome-associated malignancies and confers susceptibility to immune checkpoint inhibitors (ICIs), such as pembrolizumab. In endometrial cancers, long-term durable responses to immunotherapy have been documented (Chan et al., 2020). Toxicities related to ICIs are frequently of autoimmune etiology including rash, thyroid dysfunction, and gastrointestinal toxicity; however, more severe toxicities have been reported in multiple organ systems (Brooks et al., 2019). In a prior publication, Tomoaia et al. described a case of lethal myocarditis in a patient receiving immunotherapy with nivolumab and ipilimumab, demonstrating the potential for catastrophic adverse effects (Tomoaia et al., 2020).
We also present a rare case of ICI-related myopathy, albeit in a Lynch syndrome patient with synchronous gynecologic malignancies. This patient experienced a durable disease response after one dose, suggesting that severe toxicity might be an indicator of enduring immune modulation and extended disease control.
2 Case Report
Our patient is a 33-year-old, morbidly obese (BMI 55 mg/kg2), nulliparous female with synchronous stage IA FIGO grade 2 endometrioid endometrial adenocarcinoma and stage IVB, HPV negative, moderately differentiated, squamous cell carcinoma of the vagina. Immunohistochemical analysis revealed loss of MSH 6 in both the vaginal and endometrial tumors with hormone receptor positivity in the endometrial mass only.
Imaging demonstrated metastatic disease to the bilateral external iliac lymph nodes, measuring 2.5 cm on the left and 2.6 cm on the right, as well as to a subcutaneous abdominal wall mass measuring 2.6 cm. On physical exam, an 8 cm exophytic mass was seen filling the vagina; biopsy of both the vaginal and abdominal wall masses showed squamous cell carcinoma. Pelvic lymph node biopsy was not performed as it would not have changed management, and it was felt that whichever primary had metastasized as far as the abdominal wall was likely to also be the one involving the pelvic nodes. Furthermore, the nodes were not easily accessible via a radiologic-guided procedure. In order to preserve fertility, a levonorgestrel-releasing intrauterine device was placed for treatment of her endometrial carcinoma, while systemic chemotherapy was started with intravenous (IV) cisplatin 50 mg/m2, paclitaxel 135 mg/m2, and bevacizumab 15 mg/kg given on a 21-day cycle. After three cycles, the vaginal mass had dwindled in size to 3 cm and was subsequently excised. Dilation and curettage was also performed. Neither specimen showed residual malignancy or dysplasia. Given her initial tolerance of chemotherapy and good response, 3 additional cycles of paclitaxel, bevacizumab, and cisplatin were planned. However, cisplatin was dropped for the 6th cycle due to cisplatin toxicity. Positron emission technology (PET) scan showed disappearance of the left inguinal lymph node and decrease of the right inguinal lymph node to 1.8 cm. The abdominal wall mass had similarly decreased in size to 1.2 cm upon completion of cytotoxic chemotherapy.
We started IV pembrolizumab 200 mg after germline analysis confirmed a diagnosis of Lynch syndrome with a pathogenic mutation in MSH 6 (c2150_2153delTGAG). Eleven days after her first infusion, she presented with rapidly progressive proximal muscle weakness rendering her unable to walk. There were no other neurologic deficits including ptosis or diplopia. Blood work subsequently showed creatinine kinase (CK) of 16,280 U/L, strongly suggestive of rhabdomyolysis. Additionally, transaminases were elevated to 421 U/L (aspartate transaminase) and 156 U/L (alanine transaminase) with C-reactive protein elevated to 13.8 mg/L and erythrocyte sediment rate to 38 mm/hr. She was admitted for 11 days for aggressive fluid hydration with normal saline at 230 mL/hr and IV solumedrol 125 mg three times daily for 3 days. Fluids and steroids were tapered as her CK decreased (Fig. 1). Rheumatology and neurology evaluated her for alternative etiologies including infection, hypothyroidism, myasthenia gravis, polymyositis, and Guillain-Barre Syndrome. TSH, electrolytes, and full auto-immune work-up were negative. Thus, she was presumptively diagnosed with common terminology criteria for adverse events grade 3 ICI-induced myositis. She received a 6-week prednisone taper on discharge, at which point CK had decreased to 271 U/L and she had returned to her prior functional status.Fig. 1 Serum creatinine kinase trend (U/L) during admission while undergoing treatment; Peak value 16,280 U/L, Nadir value 51 U/L. Figure shows return to baseline in 9 days from beginning treatment.
PET scan performed one month after hospital discharge demonstrated a partial response. Twenty months following a single pembrolizumab infusion, her exams, pap smears and endometrial biopsies remain normal. Her abdominal wall mass has resolved on the most recent PET (Fig. 2A) and the right pelvic lymph node which remains, now measuring 1 cm, has decreased both in size and metabolic activity (Fig. 2B). She is currently awaiting fertility planning with reproductive endocrinology.Fig. 2 (A) Pre-ICI PET-CT (left) shows metastasis to anterior abdominal wall 1.2 × 1.0 cm with SUV 6.4, with disappearance of this lesion on 20 month post-treatment scan (right); (B) Pre-ICI PET CT shows right external iliac lymph node with prominent hypermetabolism, 1.8 × 2.0 cm with SUV 12.5; 20 month post-treatment (right) shows decrease to 1.0 x 1.1cm with SUV 3.1.
3 Discussion
The above case is the first report describing severe immune-mediated myositis after a single dose of pembrolizumab. Katsuya et al. encountered severe myositis with CK elevated to >27,000 U/L only 10 days after the first infusion; however, this was attributed to nivolumab (Sakai et al., 2017). It is unclear if the same toxicity profiles apply to both nivolumab and pembrolizumab. Ours is also the first case to describe myositis in a patient with gynecologic cancer, as most reports focus on lung cancer or melanoma. It is especially surprising to see such a severe reaction in a young, healthy woman without prior medical conditions.
Interestingly, literature more frequently cites the co-occurrence of ICI-induced myopathies with other immune-mediated toxicity. Myositis is more often described accompanied by myasthenia gravis or cardiomyopathy, leading to respiratory failure (Shirai et al., 2016, Pourhassan et al., 2019). In these instances, myositis often portends poor outcomes (Shirai et al., 2016, Pourhassan et al., 2019). Myositis occurring in isolation, while more atypical, may be less grave.
There have been reports of full recovery, though these are the minority of cases (Min and Hodi, 2014). One case series detailed 6 patients, all with immune-mediated myositis after ICI therapy: 2 died, 3 made complete recoveries, and 1 was able to continue with ICI therapy (Shah et al., 2019). The 4 patients who improved had isolated myositis and did not show symptoms of cardiopulmonary disease.
Lastly, this case describes a potent and durable response to immunotherapy. Most authors describe death or progression of disease following ICI-induced myopathy. Min and colleagues are the only other group we found to describe durable response to immunotherapy following immune toxicity, however that was in the case of melanoma after 5 doses of nivolumab (Min and Hodi, 2014). No such responses have previously been seen in patients with gynecologic cancer or after a single dose of ICI. Liewluck et al. recounted one patient found to have no viable tumor on autopsy after pembrolizumab-induced myositis; however, that patient passed due to side effects, making tumor progression, in this case, clinically irrelevant (Liewluck et al., 2018).
In a review of 576 patients, Weber et all reported an association between immune-related side effects and improved response, noting greatest benefit in patients experiencing 3 or more immune-related toxicities, though with no impact on progression free survival (Weber et al., 2017). Our case supports the correlation between disease response and autoimmune side effects.
This report documents rhabdomyolysis as a rare adverse effect of pembrolizumab. This patient has stable disease, is no longer on any therapy, and is able to pursue fertility options. Such a robust response following one cycle of ICI adds to the evidence that severe toxicity, such as rhabdomyolysis, may be a corollary for excellent response to therapy and may represent sustained tumor-immunity. The repercussions of a reaction such as myositis may, in the long run, be a favorable trade-off if disease is significantly impacted.
Funding support
Ensign Endowment for Gynecologic Cancer Research (K.M.)
CRediT authorship contribution statement
Varun Khetan: Data curation, Writing - original draft. Erin A. Blake: Data curation. Marcia A. Ciccone: Conceptualization, Data curation, Formal analysis. Koji Matsuo: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | LEVONORGESTREL?RELEASING INTRAUTERINE DEVICE | DrugDosageText | CC BY-NC-ND | 33511262 | 18,969,398 | 2021-02 |
What was the dosage of drug 'PACLITAXEL'? | Rhabdomyolysis following single administration of pembrolizumab: Is severe immune-reaction a marker for durable treatment response?
•Immune checkpoint inhibitors are approved for all mismatch repair deficient tumors.•Although rare, autoimmune myositis complicating pembrolizumab therapy may be fatal.•In this case, pembrolizumab caused rhabdomyolysis but also a durable response.•Severe autoimmune reaction may be associated with durable treatment response.
1 Background
Mismatch repair deficiency defines Lynch syndrome-associated malignancies and confers susceptibility to immune checkpoint inhibitors (ICIs), such as pembrolizumab. In endometrial cancers, long-term durable responses to immunotherapy have been documented (Chan et al., 2020). Toxicities related to ICIs are frequently of autoimmune etiology including rash, thyroid dysfunction, and gastrointestinal toxicity; however, more severe toxicities have been reported in multiple organ systems (Brooks et al., 2019). In a prior publication, Tomoaia et al. described a case of lethal myocarditis in a patient receiving immunotherapy with nivolumab and ipilimumab, demonstrating the potential for catastrophic adverse effects (Tomoaia et al., 2020).
We also present a rare case of ICI-related myopathy, albeit in a Lynch syndrome patient with synchronous gynecologic malignancies. This patient experienced a durable disease response after one dose, suggesting that severe toxicity might be an indicator of enduring immune modulation and extended disease control.
2 Case Report
Our patient is a 33-year-old, morbidly obese (BMI 55 mg/kg2), nulliparous female with synchronous stage IA FIGO grade 2 endometrioid endometrial adenocarcinoma and stage IVB, HPV negative, moderately differentiated, squamous cell carcinoma of the vagina. Immunohistochemical analysis revealed loss of MSH 6 in both the vaginal and endometrial tumors with hormone receptor positivity in the endometrial mass only.
Imaging demonstrated metastatic disease to the bilateral external iliac lymph nodes, measuring 2.5 cm on the left and 2.6 cm on the right, as well as to a subcutaneous abdominal wall mass measuring 2.6 cm. On physical exam, an 8 cm exophytic mass was seen filling the vagina; biopsy of both the vaginal and abdominal wall masses showed squamous cell carcinoma. Pelvic lymph node biopsy was not performed as it would not have changed management, and it was felt that whichever primary had metastasized as far as the abdominal wall was likely to also be the one involving the pelvic nodes. Furthermore, the nodes were not easily accessible via a radiologic-guided procedure. In order to preserve fertility, a levonorgestrel-releasing intrauterine device was placed for treatment of her endometrial carcinoma, while systemic chemotherapy was started with intravenous (IV) cisplatin 50 mg/m2, paclitaxel 135 mg/m2, and bevacizumab 15 mg/kg given on a 21-day cycle. After three cycles, the vaginal mass had dwindled in size to 3 cm and was subsequently excised. Dilation and curettage was also performed. Neither specimen showed residual malignancy or dysplasia. Given her initial tolerance of chemotherapy and good response, 3 additional cycles of paclitaxel, bevacizumab, and cisplatin were planned. However, cisplatin was dropped for the 6th cycle due to cisplatin toxicity. Positron emission technology (PET) scan showed disappearance of the left inguinal lymph node and decrease of the right inguinal lymph node to 1.8 cm. The abdominal wall mass had similarly decreased in size to 1.2 cm upon completion of cytotoxic chemotherapy.
We started IV pembrolizumab 200 mg after germline analysis confirmed a diagnosis of Lynch syndrome with a pathogenic mutation in MSH 6 (c2150_2153delTGAG). Eleven days after her first infusion, she presented with rapidly progressive proximal muscle weakness rendering her unable to walk. There were no other neurologic deficits including ptosis or diplopia. Blood work subsequently showed creatinine kinase (CK) of 16,280 U/L, strongly suggestive of rhabdomyolysis. Additionally, transaminases were elevated to 421 U/L (aspartate transaminase) and 156 U/L (alanine transaminase) with C-reactive protein elevated to 13.8 mg/L and erythrocyte sediment rate to 38 mm/hr. She was admitted for 11 days for aggressive fluid hydration with normal saline at 230 mL/hr and IV solumedrol 125 mg three times daily for 3 days. Fluids and steroids were tapered as her CK decreased (Fig. 1). Rheumatology and neurology evaluated her for alternative etiologies including infection, hypothyroidism, myasthenia gravis, polymyositis, and Guillain-Barre Syndrome. TSH, electrolytes, and full auto-immune work-up were negative. Thus, she was presumptively diagnosed with common terminology criteria for adverse events grade 3 ICI-induced myositis. She received a 6-week prednisone taper on discharge, at which point CK had decreased to 271 U/L and she had returned to her prior functional status.Fig. 1 Serum creatinine kinase trend (U/L) during admission while undergoing treatment; Peak value 16,280 U/L, Nadir value 51 U/L. Figure shows return to baseline in 9 days from beginning treatment.
PET scan performed one month after hospital discharge demonstrated a partial response. Twenty months following a single pembrolizumab infusion, her exams, pap smears and endometrial biopsies remain normal. Her abdominal wall mass has resolved on the most recent PET (Fig. 2A) and the right pelvic lymph node which remains, now measuring 1 cm, has decreased both in size and metabolic activity (Fig. 2B). She is currently awaiting fertility planning with reproductive endocrinology.Fig. 2 (A) Pre-ICI PET-CT (left) shows metastasis to anterior abdominal wall 1.2 × 1.0 cm with SUV 6.4, with disappearance of this lesion on 20 month post-treatment scan (right); (B) Pre-ICI PET CT shows right external iliac lymph node with prominent hypermetabolism, 1.8 × 2.0 cm with SUV 12.5; 20 month post-treatment (right) shows decrease to 1.0 x 1.1cm with SUV 3.1.
3 Discussion
The above case is the first report describing severe immune-mediated myositis after a single dose of pembrolizumab. Katsuya et al. encountered severe myositis with CK elevated to >27,000 U/L only 10 days after the first infusion; however, this was attributed to nivolumab (Sakai et al., 2017). It is unclear if the same toxicity profiles apply to both nivolumab and pembrolizumab. Ours is also the first case to describe myositis in a patient with gynecologic cancer, as most reports focus on lung cancer or melanoma. It is especially surprising to see such a severe reaction in a young, healthy woman without prior medical conditions.
Interestingly, literature more frequently cites the co-occurrence of ICI-induced myopathies with other immune-mediated toxicity. Myositis is more often described accompanied by myasthenia gravis or cardiomyopathy, leading to respiratory failure (Shirai et al., 2016, Pourhassan et al., 2019). In these instances, myositis often portends poor outcomes (Shirai et al., 2016, Pourhassan et al., 2019). Myositis occurring in isolation, while more atypical, may be less grave.
There have been reports of full recovery, though these are the minority of cases (Min and Hodi, 2014). One case series detailed 6 patients, all with immune-mediated myositis after ICI therapy: 2 died, 3 made complete recoveries, and 1 was able to continue with ICI therapy (Shah et al., 2019). The 4 patients who improved had isolated myositis and did not show symptoms of cardiopulmonary disease.
Lastly, this case describes a potent and durable response to immunotherapy. Most authors describe death or progression of disease following ICI-induced myopathy. Min and colleagues are the only other group we found to describe durable response to immunotherapy following immune toxicity, however that was in the case of melanoma after 5 doses of nivolumab (Min and Hodi, 2014). No such responses have previously been seen in patients with gynecologic cancer or after a single dose of ICI. Liewluck et al. recounted one patient found to have no viable tumor on autopsy after pembrolizumab-induced myositis; however, that patient passed due to side effects, making tumor progression, in this case, clinically irrelevant (Liewluck et al., 2018).
In a review of 576 patients, Weber et all reported an association between immune-related side effects and improved response, noting greatest benefit in patients experiencing 3 or more immune-related toxicities, though with no impact on progression free survival (Weber et al., 2017). Our case supports the correlation between disease response and autoimmune side effects.
This report documents rhabdomyolysis as a rare adverse effect of pembrolizumab. This patient has stable disease, is no longer on any therapy, and is able to pursue fertility options. Such a robust response following one cycle of ICI adds to the evidence that severe toxicity, such as rhabdomyolysis, may be a corollary for excellent response to therapy and may represent sustained tumor-immunity. The repercussions of a reaction such as myositis may, in the long run, be a favorable trade-off if disease is significantly impacted.
Funding support
Ensign Endowment for Gynecologic Cancer Research (K.M.)
CRediT authorship contribution statement
Varun Khetan: Data curation, Writing - original draft. Erin A. Blake: Data curation. Marcia A. Ciccone: Conceptualization, Data curation, Formal analysis. Koji Matsuo: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | 21?DAY CYCLE | DrugDosageText | CC BY-NC-ND | 33511262 | 18,969,398 | 2021-02 |
What was the outcome of reaction 'Toxicity to various agents'? | Rhabdomyolysis following single administration of pembrolizumab: Is severe immune-reaction a marker for durable treatment response?
•Immune checkpoint inhibitors are approved for all mismatch repair deficient tumors.•Although rare, autoimmune myositis complicating pembrolizumab therapy may be fatal.•In this case, pembrolizumab caused rhabdomyolysis but also a durable response.•Severe autoimmune reaction may be associated with durable treatment response.
1 Background
Mismatch repair deficiency defines Lynch syndrome-associated malignancies and confers susceptibility to immune checkpoint inhibitors (ICIs), such as pembrolizumab. In endometrial cancers, long-term durable responses to immunotherapy have been documented (Chan et al., 2020). Toxicities related to ICIs are frequently of autoimmune etiology including rash, thyroid dysfunction, and gastrointestinal toxicity; however, more severe toxicities have been reported in multiple organ systems (Brooks et al., 2019). In a prior publication, Tomoaia et al. described a case of lethal myocarditis in a patient receiving immunotherapy with nivolumab and ipilimumab, demonstrating the potential for catastrophic adverse effects (Tomoaia et al., 2020).
We also present a rare case of ICI-related myopathy, albeit in a Lynch syndrome patient with synchronous gynecologic malignancies. This patient experienced a durable disease response after one dose, suggesting that severe toxicity might be an indicator of enduring immune modulation and extended disease control.
2 Case Report
Our patient is a 33-year-old, morbidly obese (BMI 55 mg/kg2), nulliparous female with synchronous stage IA FIGO grade 2 endometrioid endometrial adenocarcinoma and stage IVB, HPV negative, moderately differentiated, squamous cell carcinoma of the vagina. Immunohistochemical analysis revealed loss of MSH 6 in both the vaginal and endometrial tumors with hormone receptor positivity in the endometrial mass only.
Imaging demonstrated metastatic disease to the bilateral external iliac lymph nodes, measuring 2.5 cm on the left and 2.6 cm on the right, as well as to a subcutaneous abdominal wall mass measuring 2.6 cm. On physical exam, an 8 cm exophytic mass was seen filling the vagina; biopsy of both the vaginal and abdominal wall masses showed squamous cell carcinoma. Pelvic lymph node biopsy was not performed as it would not have changed management, and it was felt that whichever primary had metastasized as far as the abdominal wall was likely to also be the one involving the pelvic nodes. Furthermore, the nodes were not easily accessible via a radiologic-guided procedure. In order to preserve fertility, a levonorgestrel-releasing intrauterine device was placed for treatment of her endometrial carcinoma, while systemic chemotherapy was started with intravenous (IV) cisplatin 50 mg/m2, paclitaxel 135 mg/m2, and bevacizumab 15 mg/kg given on a 21-day cycle. After three cycles, the vaginal mass had dwindled in size to 3 cm and was subsequently excised. Dilation and curettage was also performed. Neither specimen showed residual malignancy or dysplasia. Given her initial tolerance of chemotherapy and good response, 3 additional cycles of paclitaxel, bevacizumab, and cisplatin were planned. However, cisplatin was dropped for the 6th cycle due to cisplatin toxicity. Positron emission technology (PET) scan showed disappearance of the left inguinal lymph node and decrease of the right inguinal lymph node to 1.8 cm. The abdominal wall mass had similarly decreased in size to 1.2 cm upon completion of cytotoxic chemotherapy.
We started IV pembrolizumab 200 mg after germline analysis confirmed a diagnosis of Lynch syndrome with a pathogenic mutation in MSH 6 (c2150_2153delTGAG). Eleven days after her first infusion, she presented with rapidly progressive proximal muscle weakness rendering her unable to walk. There were no other neurologic deficits including ptosis or diplopia. Blood work subsequently showed creatinine kinase (CK) of 16,280 U/L, strongly suggestive of rhabdomyolysis. Additionally, transaminases were elevated to 421 U/L (aspartate transaminase) and 156 U/L (alanine transaminase) with C-reactive protein elevated to 13.8 mg/L and erythrocyte sediment rate to 38 mm/hr. She was admitted for 11 days for aggressive fluid hydration with normal saline at 230 mL/hr and IV solumedrol 125 mg three times daily for 3 days. Fluids and steroids were tapered as her CK decreased (Fig. 1). Rheumatology and neurology evaluated her for alternative etiologies including infection, hypothyroidism, myasthenia gravis, polymyositis, and Guillain-Barre Syndrome. TSH, electrolytes, and full auto-immune work-up were negative. Thus, she was presumptively diagnosed with common terminology criteria for adverse events grade 3 ICI-induced myositis. She received a 6-week prednisone taper on discharge, at which point CK had decreased to 271 U/L and she had returned to her prior functional status.Fig. 1 Serum creatinine kinase trend (U/L) during admission while undergoing treatment; Peak value 16,280 U/L, Nadir value 51 U/L. Figure shows return to baseline in 9 days from beginning treatment.
PET scan performed one month after hospital discharge demonstrated a partial response. Twenty months following a single pembrolizumab infusion, her exams, pap smears and endometrial biopsies remain normal. Her abdominal wall mass has resolved on the most recent PET (Fig. 2A) and the right pelvic lymph node which remains, now measuring 1 cm, has decreased both in size and metabolic activity (Fig. 2B). She is currently awaiting fertility planning with reproductive endocrinology.Fig. 2 (A) Pre-ICI PET-CT (left) shows metastasis to anterior abdominal wall 1.2 × 1.0 cm with SUV 6.4, with disappearance of this lesion on 20 month post-treatment scan (right); (B) Pre-ICI PET CT shows right external iliac lymph node with prominent hypermetabolism, 1.8 × 2.0 cm with SUV 12.5; 20 month post-treatment (right) shows decrease to 1.0 x 1.1cm with SUV 3.1.
3 Discussion
The above case is the first report describing severe immune-mediated myositis after a single dose of pembrolizumab. Katsuya et al. encountered severe myositis with CK elevated to >27,000 U/L only 10 days after the first infusion; however, this was attributed to nivolumab (Sakai et al., 2017). It is unclear if the same toxicity profiles apply to both nivolumab and pembrolizumab. Ours is also the first case to describe myositis in a patient with gynecologic cancer, as most reports focus on lung cancer or melanoma. It is especially surprising to see such a severe reaction in a young, healthy woman without prior medical conditions.
Interestingly, literature more frequently cites the co-occurrence of ICI-induced myopathies with other immune-mediated toxicity. Myositis is more often described accompanied by myasthenia gravis or cardiomyopathy, leading to respiratory failure (Shirai et al., 2016, Pourhassan et al., 2019). In these instances, myositis often portends poor outcomes (Shirai et al., 2016, Pourhassan et al., 2019). Myositis occurring in isolation, while more atypical, may be less grave.
There have been reports of full recovery, though these are the minority of cases (Min and Hodi, 2014). One case series detailed 6 patients, all with immune-mediated myositis after ICI therapy: 2 died, 3 made complete recoveries, and 1 was able to continue with ICI therapy (Shah et al., 2019). The 4 patients who improved had isolated myositis and did not show symptoms of cardiopulmonary disease.
Lastly, this case describes a potent and durable response to immunotherapy. Most authors describe death or progression of disease following ICI-induced myopathy. Min and colleagues are the only other group we found to describe durable response to immunotherapy following immune toxicity, however that was in the case of melanoma after 5 doses of nivolumab (Min and Hodi, 2014). No such responses have previously been seen in patients with gynecologic cancer or after a single dose of ICI. Liewluck et al. recounted one patient found to have no viable tumor on autopsy after pembrolizumab-induced myositis; however, that patient passed due to side effects, making tumor progression, in this case, clinically irrelevant (Liewluck et al., 2018).
In a review of 576 patients, Weber et all reported an association between immune-related side effects and improved response, noting greatest benefit in patients experiencing 3 or more immune-related toxicities, though with no impact on progression free survival (Weber et al., 2017). Our case supports the correlation between disease response and autoimmune side effects.
This report documents rhabdomyolysis as a rare adverse effect of pembrolizumab. This patient has stable disease, is no longer on any therapy, and is able to pursue fertility options. Such a robust response following one cycle of ICI adds to the evidence that severe toxicity, such as rhabdomyolysis, may be a corollary for excellent response to therapy and may represent sustained tumor-immunity. The repercussions of a reaction such as myositis may, in the long run, be a favorable trade-off if disease is significantly impacted.
Funding support
Ensign Endowment for Gynecologic Cancer Research (K.M.)
CRediT authorship contribution statement
Varun Khetan: Data curation, Writing - original draft. Erin A. Blake: Data curation. Marcia A. Ciccone: Conceptualization, Data curation, Formal analysis. Koji Matsuo: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | Recovered | ReactionOutcome | CC BY-NC-ND | 33511262 | 18,969,398 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Delirium'. | Implementation of the "awakening and breathing trials, choice of drugs, delirium management, and early exercise/mobility" bundle in the pediatric intensive care unit of tertiary hospitals in southwestern China: a cross-sectional survey.
OBJECTIVE
To investigate management and implementation of the "awakening and breathing trials, choice of drugs, delirium management, and early exercise/mobility" (ABCDE) bundle in the pediatric intensive care unit (PICU) in southwestern China.
METHODS
A self-designed questionnaire for determining implementation of the ABCDE bundle was distributed to healthcare professionals in the PICU. Multiple linear regression was used to analyze results.
RESULTS
A total of 270 questionnaires were collected. There was no significant difference in the awareness of the ABCDE bundle rate among Sichuan, Guizhou, and Yunnan workers. Only dynamic adjustment of drug dose accounted for more than half (55.5%) of "frequent implementation" and "general implementation", followed by implementation of sedation assessment, pain assessment, and spontaneous breathing trials (46.4%, 39.3%, and 35.6%, respectively). A total of 80.4% of healthcare professionals never performed screening of delirium. Multivariate analysis showed that the healthcare professionals' scores of ABCDE bundle behavior significantly differed regarding awareness of the ABCDE bundle, years of work at the hospital, the region of hospitals, and occupational category.
CONCLUSIONS
Implementation of the ABCDE bundle in the PICU in southwestern China is not sufficient. Existing problems need to be identified and a standardized sedation and analgesia management model needs to be established.
Introduction
Children who are admitted to the pediatric intensive care unit (PICU) are in a high-stress environment. Common causes of stress include the following:1 1) stress caused by trauma, infection, and other diseases, and frequent invasive procedures; 2) being separated from parents; appearance of many strange faces and instruments; noise and long lights disturbing the biological clock; 3) worry about the disease and prognosis and fear of death; and 4) various intubations and being bedridden. Interestingly, children undergoing mechanical ventilation (MV) may develop patient–ventilator dyssynchrony. This leads to difficulty in ventilation and delayed weaning, thereby affecting the clinical efficacy and also worsening the conditions. Therefore, sedation and analgesia are recommended as treatment for children undergoing MV.1–4 However, improper sedation and management of analgesia can result in harm and poor prognosis for children.5,6
Improper use of sedative and analgesic drugs is a cause of delirium. The incidence of delirium in the PICU ranges between 5% and 53%,7–9 and delirium during a hospital stay significantly increases the duration of MV, the length of hospital stay, and the cost of hospitalization.10,11 Another study suggested that anesthetics and sedatives adversely affect neurological function of pediatric patients.12 Because of damage and an unfavorable prognosis caused by improper analgesia and sedation for children with MV, appropriate strategies and interventions need to be adopted to maintain moderate analgesia and sedation and reduce the incidence of adverse consequences.
Pandharipande et al.13 first proposed the evidence-based “awakening and breathing trials, choice of drugs, delirium management, and early exercise/mobility” (ABCDE) bundle. The specific contents of this bundle include daily awakening, breathing coordination, choices of sedative or analgesic drugs, management of delirium, and early exercise. A recent prospective cohort study showed that the ABCDE bundle effectively reduced the MV time, the length of hospital stay, and the hospitalization cost.14 Currently, this strategy has been safely implemented in a large number of adult intensive care units (ICUs) worldwide with satisfactory results.15 However, at present, there is no guideline for the children’s ABCDE bundle. The ABCDE bundle requires teamwork and can be led by an experienced physician or nurse. The team usually includes physicians, nurses, respiratory therapists, rehabilitation therapists, and even psychiatrists.
Management and implementation of the ABCDE bundle in the PICU in China has not been reported. Therefore, the present survey aimed to determine the current status of implementation of the ABCDE bundle in the PICU of Class A tertiary hospitals in the southwestern provincial capitals of China to provide effective evidence for establishing a scientific sedation and analgesia management model in children.
Material and methods
Participants
The convenient sampling method was used to select 6 of 12 Class A tertiary hospitals with a PICU in the southwestern provincial capitals of China (Chengdu in Sichuan Province, Guiyang in Guizhou Province, and Kunming in Yunnan Province) from March to April 2019. An online survey of PICU healthcare professionals was performed from June to July 2019. Inclusion criteria were as follows: 1) practicing certificates of certified physicians and nurses; and 2) PICU healthcare professionals working in the hospital. Exclusion criteria were interns and residents who received standardized training and trainee physicians in the departments. The survey was reviewed by the West China Second University Hospital of Sichuan University Ethics Committee (2014SZ0004-9). Written informed consent was obtained from the participants before the study. Participation was voluntary, and anonymity and confidentiality were assured.
Assessment and measurement of the ABCDE bundle
We collected baseline information on sex, age, occupation, professional ranks and titles, education level, years of working in the hospital (<1, 1–2, 3–5, 6–10, and ≥11 years), years of working in the PICU (<1, 1–2, 3–5, 6–10, and ≥11 years), and regions of the hospital.
Implementation of the ABCDE bundle was based on the relevant literature worldwide and the Experts’ Consensus on Sedation and Analgesia for Children in Pediatric Intensive Care Unit of China (2018)1. We used a self-designed questionnaire that included nine items, such as daily awakening, also known as spontaneous awakening trials (SATs), spontaneous breathing trials (SBTs), drug selection and adjustment, assessment of the risk of delirium, and early exercise. The Likert grade 4 scoring standard was used (never implemented=1, occasionally implemented [implemented in <25% of children]=2, frequent implementation [25%–75% of children]=3, and general implementation [>75% of children]=4). Selection of participants was made on the basis of experience of the subjects within 3 months. The sum of the scores was calculated to assess implementation of the ABCDE bundle; the total score was 36 points and a higher score indicated better compliance with the ABCDE bundle. This questionnaire was evaluated and reviewed by five experts of critical care medicine at the Department of Critical Care Medicine, West China Second University Hospital of Sichuan University. Additionally, the content validity index was 0.781. Twenty-five nurses and five physicians were randomly selected from the Department of Critical Care Medicine, West China Second University Hospital of Sichuan University to conduct a pre-survey and calculate the Cronbach’s alpha as 0.723. Other assessments included analgesia, commonly used pain assessment scales, commonly used sedatives and analgesics, delirium management status, and non-drug interventions.
Quality control
The questionnaire was initially developed on the basis of a literature review. The Delphi method was used two times on the five experts of critical care medicine to determine the final questionnaire. A pre-survey was conducted to improve the contents of the questionnaire on the basis of existing problems. In the implementation stage, the personnel in charge of the project went to the site to conduct unified training for respondents in each hospital, and the inclusion, exclusion, and the questionnaire filling out criteria were determined. Participants logged in to the https://jinshuju.net questionnaire survey site and filled out the online questionnaire. The questionnaire used an online anonymous survey mode to ensure that the data were objective and true. The integrity and logic of the collected questionnaire were checked. Questionnaires with no logical loopholes or distinct regularity were considered valid, and those with >20% missing options were invalid.
Statistical analysis
Statistical analysis was performed using IBM SPSS 19.0 software (IBM Corp., Armonk, NY, USA). Measurement data with a normal distribution are shown as mean ± standard deviation. Between-group comparisons were made by the t-test and comparisons among more than two groups were made by the least significant difference test t-test. Data that did not conform to a normal distribution are shown as median (95% confidence intervals), and comparison between groups was performed by a non-parametric test. Count data are described by the number of cases (percentage), and comparison between groups was made by the chi-square test. P values <0.05 (two-sided) were considered statistically significant. The multiple linear regression model (stepwise method) was used to analyze factors that affected the score of ABCDE bundle behavior of the healthcare professionals. The total score of ABCDE bundle behavior was used as the dependent variable. Statistically significant variables in bivariate analysis were used as independent variables to construct the regression equation. Factors with P<0.05 in bivariate analysis were used for further analysis in multiple linear regression, and unordered multicategory variables were entered into the multiple linear regression model as dummy variables.
Results
Baseline data
A total of 270 (90%) questionnaires were collected from 300 eligible healthcare professionals. The cohort consisted of 31 (11.5%) men and 239 (88.5%) women, and the mean age was 30.23±7.58 years. Of the 60 (22.2%) physicians and 210 (77.8%) nurses, 164 (60.7%) were assistant doctor/nurse aides (junior professional title), 75 (27.8%) were doctors in charge/nurses in charge (middle-rank professional title), and 31 (11.5%) were Associate Professors of medicine/Associate Professors of nursing or Professors of medicine/Professors of nursing (senior professional title). The cohort consisted of 72 (26.7%) participants with junior college education or below, 177 (65.5%) with a university degree, and 21 (7.8%) with graduate degree or above. Furthermore, 117 (43.3%) participants were in Sichuan, 76 (28.1%) in Guizhou, and 77 (28.5%) in Yunnan.
Status of clinical implementation of the ABCDE bundle for healthcare professionals
The mean score of the healthcare professionals was 19.74±5.47 points. Only dynamic adjustment of drug dose accounted for more than half (55.5%) of “frequent implementation” and “general implementation,” followed by implementation of sedation assessment, pain assessment, and SBTs (46.4%, 39.3%, and 35.6%, respectively). A total of 80.4% of the healthcare professionals never performed assessment of the risk of delirium (Table 1).
Table 1. Status of clinical implementation of the awakening and breathing trials, choice of drugs, delirium management, and early exercise/mobility bundle for healthcare professionals (n = 270).
Item Never, n (%) Occasionally, n (%) Frequently, n (%) Generally, n (%)
SATs 48 (17.8) 153 (56.7) 49 (18.1) 20 (7.4)
SBTs 44 (16.3) 130 (48.1) 68 (25.2) 28 (10.4)
Implementation of SBTs after SATs 59 (21.9) 147 (54.4) 43 (15.9) 21 (7.8)
Sedation assessment scale 90 (33.3) 54 (20.0) 46 (17.0) 80 (29.6)
Pain assessment scale 75 (27.8) 89 (33.0) 27 (10.0) 79 (29.3)
Dynamic adjustment of drug dose 42 (15.6) 785 (28.9) 77 (28.5) 73 (27.0)
Assessment of the risk of delirium 217 (80.4) 50 (18.5) 3 (1.1) 0 (0)
Participation of early exercise in the Rehabilitation Department 104 (38.5) 97 (35.9) 47 (17.4) 22 (8.1)
Participation of early exercise of healthcare professionals 43 (15.9) 95 (35.2) 77 (28.5) 55 (20.4)
SATs, spontaneous awakening trials; SBTs, spontaneous breathing trials.
The overall awareness rate of the ABCDE bundle was 53.7%. The awareness rate of the ABCDE bundle was 56.4% in Sichuan, 47.4% in Guizhou, and 55.8% in Yunnan, with no significant difference among the three regions (P=0.425). The most common sedation assessment scale was Ramsay and that for pain assessment was the Faces Pain Scale. The most commonly used sedative and analgesic was midazolam and sufentanil, respectively. The most commonly used delirium assessment scale was the Pediatric Confusion Assessment Method for the ICU, the most common intervention drug for delirium was haloperidol, and reducing noise and light was a common non-drug intervention (Table 2).
Table 2. Common consciousness, pain, and delirium assessment scales and the distribution of drugs.
Item Sichuan (n = 117), n (%) Guizhou (n = 76), n (%) Yunnan (n = 77), n (%) Total (n = 270), n (%)
Most commonly used sedation assessment scales
COMFORT score 12 (13.8) 20 (45.5) 8 (16.3) 40 (22.2)
COMFORT-B score 7 (8.0) 8 (18.2) 4 (8.2) 19 (10.6)
Ramsay score 63 (72.4) 5 (11.4) 24 (49.0) 92 (51.1)
SAS 15 (17.2) 9 (20.5) 9 (18.4) 33 (18.3)
RASS 12 (13.8) 12 (27.3) 12 (24.5) 36 (20.0)
BIS 1 (1.1) 3 (6.8) 10 (20.4) 14 (7.8)
Others 3 (3.4) 7 (15.9) 6 (12.2) 16 (8.9)
Most commonly used pain assessment scales
NRS 24 (29.3) 4 (7.7) 20 (32.8) 48 (24.6)
VRS 5 (6.1) 1 (1.9) 8 (13.1) 14 (7.2)
VAS 11 (13.4) 1 (1.9) 12 (19.7) 24 (12.3)
FPS 44 (53.7) 26 (50.0) 44 (72.1) 114 (58.5)
FLACC 20 (24.4) 27 (51.9) 32 (52.5) 79 (40.5)
CRIES 19 (23.2) 4 (7.7) 8 (13.1) 31 (15.9)
CHEOPS 1 (1.2) 0 0 1 (0.5)
Others 2 (2.4) 1 (1.9) 1 (1.6) 4 (2.1)
Most commonly used sedatives
Diazepam 62 (53.0) 20 (26.3) 27 (35.1) 109 (40.4)
Midazolam 115 (98.3) 76 (100.0) 77 (100.0) 268 (99.3)
Phenobarbital 75 (64.1) 55 (72.4) 20 (26.0) 150 (55.6)
Dexmedetomidine 67 (57.3) 49 (64.5) 14 (18.2) 130 (48.1)
Chloral hydrate 74 (63.2) 28 (36.8) 69 (89.6) 171 (63.3)
Propofol 50 (42.7) 10 (13.2) 29 (37.7) 89 (33.0)
Most commonly used analgesics
Morphine 48 (41.0) 2 (2.6) 5 (6.5) 55 (20.4)
Fentanyl 43 (36.8) 18 (23.7) 64 (83.1) 125 (46.3)
Sufentanil 77 (65.8) 45 (59.2) 21 (27.3) 143 (53.0)
Remifentanil 16 (13.7) 21 (27.6) 8 (10.4) 45 (16.7)
Acetaminophen 13 (11.1) 10 (13.2) 37 (48.1) 60 (22.2)
Ibuprofen 15 (12.8) 25 (32.9) 57 (74.0) 97 (35.9)
Common assessment scales for delirium
pCAM-ICU 16 (84.2) 13 (61.9) 10 (76.9) 39 (73.6)
CAPD 3 (15.8) 1 (4.8) 0 4 (7.5)
PAED 4 (21.1) 1 (4.8) 3 (23.1) 8 (15.1)
ICDSC 6 (31.6) 6 (11.3) 0 12 (22.6)
Common intervention drugs for delirium
Haloperidol 14 (73.7) 10 (47.6) 13 (100.0) 37 (69.8)
Risperidone 1 (5.3) 10 (47.6) 0 11 (20.8)
Olanzapine 6 (31.6) 0 0 6 (11.3)
Others 1 (5.3) 1 (4.8) 0 2 (3.8)
Non-drug interventions
Reducing noise and light 60 (95.2) 20 (100.0) 28 (77.8) 108 (90.8)
Reducing night stimulation 54 (85.7) 16 (80.0) 28 (77.8) 98 (82.4)
Distraction 43 (68.3) 19 (95.0) 16 (44.4) 78 (65.5)
Hypnosis 12 (19.0) 1 (5.0) 8 (22.2) 21 (17.6)
Centralized nursing procedures 55 (87.3) 15 (75.0) 31 (86.1) 101 (84.9)
SAS, Riker sedation-anxiety score; RASS, Richmond agitation and sedation score; BIS, bispectral index; NRS: numerical rating scale; VRS, verbal rating scale; VAS, visual analog scale; FPS, faces pain scale; FLACC, face, legs, activity, crying, consolability; CRIES, crying, requires O2 saturation, increased vital signs, expression, sleeplessness; CHEOPS, cry, facial, child verbal, torso, touch, legs; pCAM-ICU, Pediatric Confusion Assessment Method for the ICU; CAPD, Cornell Assessment of Pediatric Delirium; PAED, pediatric anesthesia emergence delirium; ICDSC, intensive care delirium screening checklist.
Analysis of factors affecting ABCDE bundle behavior
Bivariate analysis of factors affecting ABCDE bundle behavior
Bivariate analysis showed significant differences in the scores of ABCDE bundle behavior for sex, occupation category, professional ranks and titles, working years in the hospital, working years in the PICU, regions of the hospital, and understanding of the ABCDE bundle (all P<0.05) (Table 3).
Table 3. Bivariate analysis of scores of ABCDE bundle behavior for healthcare professionals (n = 270).
Group n Behavior score (mean ± SD)
P
Sex
Men 31 20.01 ± 5.79 0.025
Women 239 17.68 ± 5.38
Occupation
Physician 60 17.75 ± 6.44 0.006
Nurse 210 20.31 ± 5.03
Professional rank and title
Junior professional title 164 20.85 ± 5.23 <0.001a
Middle-rank professional title 75 17.61 ± 4.49
Senior professional title 31 19.03 ± 7.16
Educational level
College and below 72 20.58 ± 5.08 0.159
Undergraduate 177 19.28 ± 5.43
Postgraduate and above 21 20.76 ± 6.73
Years of working in the hospital
<1 year 34 22.30 ± 5.18 0.001b
1–2 years 44 20.39 ± 5.87
3–5 years 52 21.77 ± 4.86
6–10 years 62 18.39 ± 4.70
≥11 years 78 18.00 ± 5.47
Working years in the PICU
<1 year 89 21.46 ± 5.70 0.003c
1–2 years 38 19.53 ± 5.05
3–5 years 81 19.31 ± 5.24
6–10 years 36 18.11 ± 4.15
≥11 years 26 17.81 ± 6.23
Regions of the hospital
Sichuan 117 21.28 ± 5.54 <0.001d
Guizhou 76 18.26 ± 5.26
Yunnan 77 18.87 ± 5.00
Understanding of the ABCDE bundle
Yes 145 21.26 ± 5.19 <0.001
No 125 17.98 ± 5.27
aSignificant difference between junior and middle-rank professional titles (P<0.05). There was no significant difference between junior professional and senior professional titles (P = 0.080) or between middle-rank and senior professional titles (P = 0.211).
bSignificant difference between healthcare professionals who worked at the hospital for 6 to 10 years and those who worked for <1 and 3 to 5 years (both P<0.05); significant difference between healthcare professionals who worked in the hospital for ≥11 years and those who worked for <1, 1 to 2, and 3 to 5 years (all P<0.05).
cSignificant difference between healthcare professionals who worked in the PICU for <1 year and those who worked for 3 to 5, 6 to 10, and ≥11 years (all P<0.05).
dSignificant difference among Sichuan, Guizhou, and Yunnan Provinces (all P<0.05), but no difference between Guizhou and Yunnan Provinces (P = 0.481).
SD, standard deviation; PICU, pediatric intensive care unit; ABCDE bundle, awakening and breathing trials, choice of drugs, delirium management, and early exercise/mobility.
Multivariate analysis of factors affecting ABCDE bundle behavior
The multiple regression equation included the following: the region of the hospital (Sichuan = [0, 0, 0], Guizhou = [0, 1, 0], Yunnan = [0, 0, 1); understanding of the ABCDE bundle (yes = 1, no = 2); working years in the hospital (<1 year = 1, 1–2 years = 2, 3–5 years = 3, 6–10 years = 4, and ≥11 years = 5); and occupational category (nurse = 0, physician = 1). Multivariate analysis showed that the healthcare professionals’ scores of ABCDE bundle behavior significantly differed in terms of awareness of the ABCDE bundle, years of work at the hospital, the region of hospitals, and occupational category (all P < 0.05, Table 4).
Table 4. Factors associated with awakening and breathing trials, choice of drugs, delirium management, and early exercise/mobility bundle behavior using multivariable analysis.
Variable B SE
P
Adjusted R2
Understanding of bundle management −3.502 −0.320 0.001 0.230
Years of working in the hospital −1.041 −0.263 0.001
Guizhou −2.786 −0.230 0.001
Yunnan −1.704 −0.141 0.019
Occupation category −1.526 −0.116 0.046
B, standardized partial regression coefficient; SE, standard error.
Discussion
Approximately half of the respondents in this study were not aware of the ABCDE bundle strategy, which is similar to data (58.4%) from a survey of nurses in Italy.16 This finding indicates that the relevant knowledge reserve and update of healthcare professionals require improvement by training to strengthen the scientific management of sedation and analgesia. A recent survey of global adult ICUs showed that the proportion of implementing daily routine awakening and SBTs was 59% and 67%, respectively.15 Additionally, 42% of the respondents reported that they would use SATs and SBTs simultaneously. The proportion of routine use of the pain assessment scale and sedation scale was 83% and 89%, respectively. In our study, in addition to dynamically adjusting the dose of drugs, the proportion of the remaining ABCDE bundle procedures in “frequent implementation” and “general implementation” was less than 50% and greatly lagged behind the international adult ICU level. This phenomenon could be attributed to the current severe shortage of medical resources of pediatric critical care medicine and healthcare professionals who are involved in the daily resuscitation of critical children and recovery of diseases and organ function. Therefore, implementing sedation and analgesia management clinically is difficult. The provincial capital is usually a regional gathering center of high-quality medical resources, which can largely reflect the medical level in the region. However, based on the survey of our study, implementation of the ABCDE bundle in the southwestern provincial capitals could be improved, which should attract attention from medical nursing colleges of pediatric critical care medicine. Moreover, allocation of human resources should be strengthened, and medical nursing procedures of the PICU should be scientifically implemented.
Delirium significantly increases the MV time, length of hospital stay, and hospitalization costs, and is independently related to mortality.7,17,18 Delirium may also be manifested as post-traumatic stress disorder, depression, anxiety, and change in future cognitive function after discharge.19 Although numerous studies have emphasized the need for screening and intervention of delirium in critical children, clinical implementation in the PICU has not yet been achieved. The proportion of never implementing delirium screening in the current study was 80.4%, which is much higher than that in a Chinese report on the adult ICU (36.6%).20 Only 1.1% of healthcare professionals reported that they would conduct assessment of delirium frequently in our study. This finding is similar to that of a PICU survey of North America that showed that only 2% of healthcare professionals routinely conducted screening of delirium twice a day.21 Because children are subject to changes in language and age, assessing their delirium is challenging. The current study showed that the Pediatric Confusion Assessment Method for the ICU was the most commonly used screening tool for delirium, but this scale is only applicable to children aged >5 years.22 This is because younger children do not cooperate easily, thereby reducing compliance. In 2016, the European Society of Pediatric and Neonatal Intensive Care recommended use of the Cornell Assessment of pediatric delirium (CAPD) tool for assessing delirium in children (level of evidence A).23 This scale is adaptive to children aged 0 to 21 years or those with developmental retardation6 and a single assessment requires 2 minutes, which improves compliance of children. The Children’s Hospital of Chongqing in China24 has completed Chinesization and cross-cultural adjustment of the CAPD scale. The Chinese version of the CAPD assesses the occurrence of delirium in children with strong feasibility and applicability as clinical observations. However, large-scale epidemiological data on delirium in children in China are still unavailable.
The present study showed that healthcare professionals with fewer working years and a junior professional title had higher compliance with the ABCDE bundle, which is inconsistent with survey findings by Lu et al.20 Critical care medicine is a highly specialized and rapidly developing discipline that requires continuous learning to update and acquire new knowledge and skills. Studies have shown that a lack of knowledge and awareness is a major factor affecting employees’ ABCDE bundle behavior.25,26 Healthcare professionals with less working years and a junior professional title may receive more training and are more willing to accept new concepts during recruitment. Our study also showed that the nurses’ scores of ABCDE bundle behavior were higher than those of physicians. As a population who has frequent contact with children, nurses play multiple roles as leaders, organizers, and implementers in management of the ABCDE bundle. This is consistent with the ICU survey results of a study by Zhou et al.27 However, some studies showed that, for each unit, the compliance of the ABCDE bundle was reduced by 53% as the workload increased.28 This finding suggests that managers should pay attention to the nurses’ workload and rationally allocate human resources to improve compliance of the ABCDE bundle. Additionally, some studies have shown that tedious document writing, a heavy workload, and a lack of core leaders affect implementation of the ABCDE bundle.29 Good teamwork eases implementation of the ABCDE bundle and increase the healthcare professionals’ confidence.30 Nevertheless, further investigation is required regarding the factors affecting implementation of the ABCDE bundle in the PICU in China.
The present study has human limitations and restricted financial resources. We did not include all hospitals with a PICU in the southwest of China, and the sample representation may have been biased. Additionally, this was a cross-sectional study, which only analyzed the effects on general information of healthcare professionals. Furthermore, the adjusted R2 was not high enough, which meant that there was a 23% probability that the obtained multiple linear equation was valid. Actually, healthcare professionals’ awareness was highly related to their implementation of the ABCDE bundle, but we did not conduct an in-depth study of the related influencing factors. Therefore, the factors affecting implementation of the ABCDE bundle in the PICU require further investigation.
In conclusion, implementation of the ABCDE bundle in the PICU in southwestern provincial capitals of China still lags behind that of adult ICUs. Moreover, specific implementation of the ABCDE bundle in the PICU in management of delirium worldwide is not optimistic. Therefore, the relevant managers need to pay more attention to the ABCDE bundle and analyze the existing problems of managing sedation and analgesia in the PICU. Furthermore, by combining the characteristics and existing resources in this field, a scientific and standardized sedation and analgesia management model should be established to improve the quality of medical nursing and prognosis of children.
Acknowledgements
We thank five experts of pediatric critical care medicine (Lina Qiao, MD, DeYuan Li, MD, Zhongqiang Liu, MD, Yang Wang, and Haiyang Zhang) for their help in developing and implementing this questionnaire.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was supported by the Sichuan Health and Family Planning Commission Popularization and Application Project (18PJ214).
ORCID iDs: Xiaoming Huang https://orcid.org/0000-0002-5312-2963
Min Xu https://orcid.org/0000-0002-4697-3030 | ACETAMINOPHEN, CHLORAL HYDRATE, DEXMEDETOMIDINE, DIAZEPAM, FENTANYL, IBUPROFEN, MIDAZOLAM, MORPHINE, PHENOBARBITAL, PROPOFOL, REMIFENTANIL, SUFENTANIL | DrugsGivenReaction | CC BY-NC | 33513055 | 19,607,216 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arrhythmia'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arthralgia'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood disorder'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebral infarction'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dizziness'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram QT prolonged'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram T wave abnormal'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrolyte imbalance'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal disorder'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
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Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemoptysis'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Headache'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatotoxicity'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intestinal obstruction'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neuropathy peripheral'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Optic neuritis'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ototoxicity'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Psychiatric symptom'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal injury'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Skin reaction'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Syncope'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thyroid disorder'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Upper respiratory tract infection'. | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | AMIKACIN, AMINOSALICYLIC ACID, AMOXICILLIN\CLAVULANATE POTASSIUM, BEDAQUILINE FUMARATE, CLOFAZIMINE, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LEVOFLOXACIN, LINEZOLID, MEROPENEM, MOXIFLOXACIN, PASINIAZID, PROTIONAMIDE, PYRAZINAMIDE, STREPTOMYCIN SULFATE | DrugsGivenReaction | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
What was the administration route of drug 'BEDAQUILINE FUMARATE'? | Interim Effectiveness and Safety Comparison of Bedaquiline-Containing Regimens for Treatment of Diabetic Versus Non-Diabetic MDR/XDR-TB Patients in China: A Multicenter Retrospective Cohort Study.
BACKGROUND
Diabetes mellitus (DM), a common tuberculosis (TB) comorbidity, is associated with delayed bacillary clearance during anti-TB treatment and unfavorable outcomes. Bedaquiline (BDQ), when used as part of multidrug regimen for multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB), has been shown to be effective and safe although treatment outcome and risks for patients with MDR/XDR-TB and DM are unknown. A multicenter retrospective study was conducted to compared the safety and effectiveness of 24-week BDQ-containing anti-TB treatment for patients with MDR/XDR-TB with and without DM.
METHODS
The study of patients with MDR/XDR-TB with or without DM (enrolled February 2018-September 2019, 21 Chinese hospitals) was supervised by the New Drug Introduction and Protection Program (NDIP). Of 640 patients with MDR/XDR-TB receiving BDQ-containing anti-TB treatments, two propensity score-matched groups (107 DM/107 non-DM) were compared for cumulative culture conversion rate, time to culture conversion, adverse events, and corrected QT interval.
RESULTS
Body mass index was higher in patients with DM than patients without DM (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001); lung cavity prevalence (86.9% vs. 72.9%, P = 0.037) was also higher in patients with DM; the non-DM group had higher hepatitis prevalence (29.0% vs. 15.9%, P = 0.022). No significant intergroup differences were found for sputum culture conversion rate at week 8 (80.0% vs. 81.4%, P = 0.884), at week 24 (95.6% vs. 98.2%, P = 0.629), or for median time to sputum culture conversion [56 days (IQR 28-63) vs. 56 days (IQR 28-84) (P = 0.687)]. Favorable post-24-week treatment outcomes were presented by 90.7% and 93.5% in the DM group and non-DM group, respectively, without significant intergroup differences (P = 0.448). The DM adverse event rate exceeded non-DM rate (77.6% vs. 64.5%, P = 0.035).
CONCLUSIONS
Despite some differences in baseline characteristics, Chinese patients with MDR/XDR-TB with or without DM had similar sputum culture conversion rates and favorable treatment outcomes post-24-week BDQ-containing anti-TB treatment. Low BMI but not DM is risk factor associated with unfavorable outcome of patients with MDR/XDR-TB.
Key Summary Points
Patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline.
Patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates.
All patients had acceptable safety and drug tolerability after 24 weeks of treatment.
Digital Features
This article is published with digital features, including a summary slide, to facilitate understanding of the article. To view digital features for this article go to https://doi.org/10.6084/m9.figshare.13366676.
Introduction
In 2019, 463 million people aged 20–79 were afflicted with diabetes mellitus (DM) globally according to an International Diabetes Federation (IDF) report. This number is predicted to reach 578 million and 700 million by 2030 and 2045 [1], respectively. Meanwhile, the World Health Organization (WHO) recently reported an estimated 484,000 new cases of rifampicin-resistant TB (RR-TB), of which 78% were multidrug-resistant TB (MDR-TB) cases [2]. In China, which shoulders a double burden of DM and MDR-TB cases, numbers of patients with DM reached 116.4 million in 2019, ranking first in DM prevalence worldwide [1], while estimated MDR/RR-TB prevalence reached 66,000, ranking second worldwide [2]. Notably, DM is a major risk factor for progression of latent TB to active TB; DM triples future active TB risk and doubles future MDR-TB risk [3–5]. Several studies have shown that DM negatively impacts treatment outcomes in patients with MDR-TB. Specifically, DM was associated with both delayed Mycobacterium tuberculosis clearance during anti-tuberculosis (anti-TB) treatment and with worse anti-TB treatment outcomes that were, in turn, independently associated with increased risk of treatment failure and death [6–8]. Conversely, DM treatment outcomes can be affected by TB, since DM treatment success using hypoglycemic agents for controlling blood glucose levels can be undermined by TB itself and by certain anti-TB drugs [9]. Of additional concern is that increasing co-prevalence of DM and TB may reverse decades-long progress made against TB. The WHO now recommends careful DM screening prior to anti-TB treatment initiation as interim policy [10].
Bedaquiline (BDQ), a newer agent for MDR-TB treatment that was approved by the US Food and Drug Administration in 2012, is a diarylquinoline anti-mycobacterial drug that inhibits mycobacterial adenosine triphosphate (ATP) synthase [11]. Studies have shown that adding BDQ to a standard anti-MDR-TB treatment regimen reduced the time to sputum culture conversion, increased the proportion of patients with sustained negative sputum culture results, and improved patient long-term survival [11–13]. However, recently published clinical data related to the use of BDQ in patients with pulmonary MDR-TB and DM is limited.
A cohort of patients with MDR/XDR-TB treated with a BDQ-containing anti-TB regimen under China’s New Drug Introduction and Protection Program (NDIP) was studied. The aim of the study was to assess safety and effectiveness of interim BDQ-containing anti-TB treatment in two groups of patients with MDR/XDR-TB, those with and those without type 2 DM. Intergroup comparisons were conducted to provide evidence of safety and effectiveness of BDQ-containing anti-TB regimens when administered to patients with concurrent DM and MDR/XDR-TB.
Methods
Study Participants
This retrospective study utilized an MDR/XDR-TB cohort admitted between February 2018 and September 2019 that received follow-up until the end of March 2020 in 21 hospitals across China under a project named the New Drug Introduction and Protection (NDIP) Program. With support from the China-Gates TB Control Project, NDIP was initiated in 2017 and established an effective nationwide working mechanism for the proper use of the first new anti-TB drug BDQ donated by the Global Drug Facility under an active drug safety monitoring framework. Medical professionals of selected TB specialized hospitals capable of MDR-TB diagnosis and treatment were well trained for patients enrollment, BDQ-containing regimen design and drug administration, treatment outcome and safety monitoring, and evaluation according to the NDIP protocol. A standardized electronic case report form was filled in by trained doctors in each center and data was reviewed by an independent data monitoring committee of NDIP routinely.
Patients were enrolled if they met the following eligibility. Inclusion criteria were (1) laboratory diagnosis of MDR/XDR-TB; (2) failure to respond to current MDR-TB regimens lacking bedaquiline; (3) at least 18 years of age; (4) no respiratory failure, cardiac failure, clinically significant arrhythmia, or corrected QT interval with Fridericia formula (QTcF) less than 450 ms. Exclusion criteria were (1) allergy to BDQ; (2) participation in other clinical trials within the past 3 months; (3) pregnant or breast-feeding; (4) concomitant serious illness, including alanine aminotransferase/aspartate aminotransferase (ALT/AST) greater than three times the upper limits of normal (ULN) or total bilirubin greater than two times ULN, creatinine clearance less than 30 mL/min, hemoglobin less than or equal to 7.0 g/dL and/or platelets less than 50 × 109/L at screening; (5) history of high-risk cardiac comorbidities (e.g., ventricular arrhythmia, myocardial infarction) with risk factors of QT prolongation: (a) electrocardiogram (ECG) at screening showing evident QT interval or QTcF ≥ 450 ms (an unscheduled visit was allowed for ECG re-examination during the screening period to re-evaluate patient eligibility); (b) pathologic Q wave (Q wave greater than 40 ms or depth of Q wave greater than 0.4–0.5 mV); (c) evidence of ventricular pre-excitation (e.g., Wolff–Parkinson–White syndrome); (d) ECG showed evidence of complete or clinically significant incomplete left bundle branch block or right bundle branch block; (e) evidence of grade II or III heart block; (f) intraventricular conduction delay, QRS duration greater than 120 ms; (g) bradycardia (sinus heart rate less than 50 bpm); (h) personal or family history of long QT syndrome; (i) history of heart disease, symptomatic or asymptomatic arrhythmia (except for sinus arrhythmia); (j) cardiogenic syncope; or (k) have risk factors for developing torsades de pointes (TdP), such as heart failure, hypokalemia, or hypomagnesemia. NDIP was approved by the ethics committee of each participating hospital. All patients enrolled provided written informed consent.
Treatment Regimen
According to WHO guidelines and NDIP protocol, local physicians developed individualized background regimens based on patients’ previous histories of anti-TB treatment and drug susceptibility testing (DST) results as well as drug tolerance. For patients with DST results, BDQ was used in combination with at least three background drugs to which their TB isolate was susceptible. For patients without definitive DST results, BDQ was used in combination with at least four drugs to which the isolate was likely to be susceptible on the basis of treatment history and local epidemiology of drug resistance. BDQ was administered at the recommended dose of 400 mg once a day for 14 days and then at a dose of 200 mg three times per week for the remaining 22 weeks.
Background regimens consisted of the anti-TB drug formulations guided by DST, including moxifloxacin, levofloxacin, linezolid, clofazimine, amikacin, capreomycin, protionamide, cycloserine, pyrazinamide, ethambutol, para-aminosalicylic acid, high-dose isoniazid, meropenem, and amoxicillin/clavulanate. To ensure patient adherence to outpatient treatment, patients were supervised by trained professional clinicians, who monitored patient treatment progress and provided medical and psychosocial support.
Prolongations of QTcF more than 500 ms were investigated, and treatment was modified if the prolongation was considered to be drug related by the site investigators.
Treatment Evaluation
Patients were followed every 2 weeks for the first month and every 4 weeks thereafter. Information regarding demographic characteristics, clinical history, medication history, laboratory test results, electrocardiographic (ECG) and adverse events (AEs), and bacteriological and radiological findings were collected from the NDIP information monitoring system. Monitored patient outcomes included cumulative sputum culture conversion rate, time to sputum culture conversion, adverse events (AEs), and QTcF. Culture conversion was defined as presence of a positive sputum culture result at baseline followed by at least two consecutive negative MGIT cultures of sputum taken at least 28 days apart. Time to culture conversion was defined as the time from baseline to the first negative sputum culture in patients exhibiting culture conversion. AEs were recorded during the treatment period and graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events guidelines, version 2.1 [14].
Patient outcomes at week 24 were graded as favorable if the patient had completed 24 weeks of BDQ treatment and achieved sustained sputum culture conversion without interruption of treatment, or if the patient had consistently tested sputum culture negative relative to baseline. Those who died during treatment, failed to achieve culture conversion or reversion, prematurely discontinued the study, or were otherwise lost to follow-up were deemed to have unfavorable outcomes.
Statistical Analysis
Qualitative and quantitative variables were reported in percentages with mean ± standard deviation (SD) and median interquartile range (IQR) values, as appropriate. Clinical characteristics of patients with MDR-TB with and without DM were compared between groups using chi-square test or Fisher’s exact test for categorical variables and Student’s t test or Mann–Whitney U test for continuous variables. To elucidate potential factors associated with unfavorable interim outcomes, selected variables with P values less than 0.05 as determined via univariate regression analysis were further analyzed using multivariate logistic regression with the “backward selection” method. Cox hazard proportional models were used to determine time to culture conversion results.
Patients with DM (the DM group) and patients without DM (the non-DM group) were matched in a 1:1 ratio on the basis of age, sex, and diagnosis with DST profiles using propensity score matching (PSM). Effectiveness and safety were evaluated for the matched cohort, with PSM conducted using the R software MatchIt package. Data analyses were performed using SPSS 22.0 (IBM, Armonk, NY, USA). P values less than 0.05 were considered statistically significant.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Results
Baseline Characteristics of Patients with MDR/XDR-TB with and Without DM
Of 640 patients with MDR/XDR-TB treated with BDQ-containing regimens from 21 centers of NDIP, 107 (16.7%) had type 2 DM. When PSM was used at 1:1, another 107 patients with MDR/XDR-TB without DM were matched on the basis of age, gender, and DST profiles at baseline (Table 1). Body mass index (BMI) values of patients with MDR/XDR-TB in the DM group exceeded those of the non-DM group (23.29 ± 3.9 vs. 20.5 ± 3.6, P < 0.001). Comorbid viral hepatitis infection was more common in the non-DM group (29.0% vs. 15.9%, P = 0.022). Patients with DM were more likely to have lung cavities (86.9% vs. 72.9%, P = 0.010). No statistically significant intergroup differences in other clinical characteristics at baseline (e.g., previous duration of TB illness, extrapulmonary TB, and blood albumin level, etc.) were observed (P > 0.05).Table 1 Clinical characteristics of patients with MDR/XDR-TB with or without DM at the baseline
Characteristics DM group (n = 107) Non-DM group (n = 107) P value
Mean age, years (SD) 49.8 ± 10.5 49.3 ± 9.7 0.736
Male, no. (%) 98 (91.6) 98 (91.6) > 0.999
Mean BMI, kg/m2 (SD) 23.29 ± 3.9 20.5 ± 3.6 < 0.001
Patients with previous anti-TB treatment history, no. (%) 90 (84.1) 96 (89.7) 0.224
DST profile, no. (%) > 0.999
MDR-TB 36 (33.6) 36 (33.6)
Pre-XDR-TB 39 (36.5) 39 (36.5)
XDR-TB 32 (29.9) 32 (29.9)
Median duration of TB, months (IQR) 30.0 (9.0–72.0) 44.0 (12.0–110.0) 0.170
Site of TB focus, no. (%) 0.252
Pulmonary only 103 (96.3) 98 (91.6)
Pulmonary and extrapulmonary 4 (3.7) 9 (8.4)
Lung cavities, no. (%) 0.010
Without any cavities 14 (13.1) 29 (27.1)
With at least 1 cavity 93 (86.9) 78 (72.9)
Comorbidities, no. (%)
Heart disease 4 (3.7) 3 (2.8) 0.701
Hepatitis infection 17 (15.9) 31 (29.0) 0.022
Median duration of DM, months (IQR) 72 (20–120) – N/A
DM medications, no. (%) – N/A
Insulin 56 (52.3)
Oral hypoglycemica 31 (29.0)
Both 13 (12.2)
None 7 (6.5)
Median fasting plasma glucose, mmol/L (IQR) 7.7 (5.7–9.5) – N/A
Median glycosylated hemoglobin (IQR) 7.3 (6.2–8.7) – N/A
Mean blood albumin, g/L (SD) 39.7 ± 5.9 38.7 ± 5.0 0.164
BMI body mass index, SD standard deviation, IQR interquartile range, DST drug susceptibility testing, MDR-TB multidrug-resistant tuberculosis, Pre-XDR-TB tuberculosis resistant to either a fluoroquinolone or a second-line injectable drug, XDR-TB extensively drug-resistant tuberculosis, N/A not applicable
aIncluded metformin, acarbose, and thiazolidinediones
Regarding patients with DM, median lifetime duration with DM was 72 months (IQR 20–120), median fasting plasma glucose was 7.7 mmol/L (IQR 5.7–9.5), median glycosylated hemoglobin level was 7.3 (IQR 6.2–8.7), and numbers of patients with DM using insulin, insulin plus an oral medicine, oral medicine, and diet control as DM treatments were 56 (52.3%), 31 (29.0%), 13 (12.2%), and 7 (6.5%), respectively.
Optimal Background Anti-TB Drug Regimen
As per the protocol recommended by NDIP, a median of 5 (IQR 4–5) anti-TB drugs were used to formulate the optimal background regimen, including fluoroquinolones, linezolid, clofazimine, and cycloserine as major components. Other drugs and proportions of patients receiving them are presented in Table 2, with no differences observed between groups.Table 2 Optimal background anti-TB drugs used in patients with MDR/XDR-TB with or without DM
Drugs, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Moxifloxacin 51 (47.7) 59 (55.1) 0.274
Levofloxacin 10 (9.3) 11 (10.3) 0.818
Linezolid 97 (90.7) 96 (89.7) 0.818
Clofazimine 77 (72.0) 69 (64.5) 0.240
Cycloserine 91 (85.0) 89 (83.2) 0.708
Ethambutol 12 (11.2) 9 (8.4) 0.491
Pyrazinamide 24 (22.4) 19 (17.8) 0.394
Protionamide 49 (45.8) 55 (51.4) 0.412
Amikacin 31 (29.0) 42 (39.3) 0.113
Capreomycin 22 (20.6) 25 (23.4) 0.620
p-Aminosalicylic acid 43 (40.2) 33 (30.8) 0.153
Pasiniazid 2 (1.9) 2 (1.9) > 0.999
Amoxicillin/clavulanic acid 12 (11.2) 11 (10.3) 0.825
Streptomycin 1 (0.9) 0 (0) > 0.999
Clarithromycin 3 (2.8) 0 (0) 0.246
High-dose isoniazid 2 (1.9) 1 (0.93) > 0.999
Median no. of drugs in background regimen, (IQR) 5 (4–5) 5 (4–5) 0.364
Interim Sputum Culture Conversion and Treatment Outcomes
Comparisons of sputum culture conversion rates and time to sputum culture conversion between groups are outlined in Table 3. Among 107 patients with MDR/XDR-TB in the DM group, 76 (71%) were culture positive at baseline, of which 60 (80.0%) achieved early culture conversion after 8 weeks and 66 (95.6%) completed 24 weeks of intensive treatment with sustained culture conversion. The median time to sputum culture conversion was 56 days (IQR 28–63).Table 3 Sputum culture conversion in two groups
Sputum conversion DM group Non-DM group P value
Culture conversion at 8th week, n/N (%) 60/75 (80.0) 48/59 (81.4) 0.844
Culture conversion at 24th week, n/N (%) 66/69 (95.6) 54/55 (98.2) 0.629a
Time to culture conversion, days 56.0 (28–63) 56.0 (28–84) 0.876
aFisher’s exact test is used
Among the matched 107 patients with MDR/XDR-TB in the non-DM group, 61 patients (57%) were culture positive at baseline, of which 48 (81.4%) achieved early culture conversion after 8 weeks and 54 (98.2%) eventually completed 24 weeks of intensive treatment with sustained culture conversion. The median time to conversion was also 56 days (IQR 28–84).
According to time to event analysis, no significant intergroup differences in probability of achieving culture conversion were observed by the end of the 24-week treatment period (P = 0.876; Fig. 1).Fig. 1 Kaplan–Meier plot for time to sputum culture conversion within 24 weeks
On the basis of interim treatment outcomes at 24 weeks post-treatment initiation for the 107 patients with MDR/XDR-TB in each group outlined in Table 4, including 97 (90.7%) in the DM group and 100 (93.5%) in the non-DM group, favorable outcomes with no significant intergroup differences were observed (P = 0.448). Meanwhile, 4 (3.7%) patients transferred out, 3 (2.8%) patients defaulted, and 3 (2.8%) patients experienced sputum culture reversion within 24 weeks in the DM group, with similar distributions observed for the non-DM group and no significant intergroup differences observed (P = 0.448).Table 4 Interim effectiveness of treatment in patients with MDR/XDR-TB at 24th week in two groups
Interim treatment outcome, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Favorable outcome 97 (90.7) 100 (93.5) 0.448
Sputum culture conversion 66 (61.7) 54 (50.5)
Completion 31 (29.0) 46 (43.0)
Unfavorable outcome 10 (9.3) 7 (6.5) 0.448
Death 0 (0.0) 0 (0.0)
Transfer out 4 (3.7) 4 (3.7)
Default 3 (2.8) 2 (1.9)
Sputum culture reversion 3 (2.8) 1 (0.9)
Multivariable logistic regression analysis showed that DM comorbidity was not associated with unfavorable treatment outcomes at the end of 24 weeks [odds ratio (OR) 1.169, 95% confidence interval (CI) 0.417–3.276, P = 0.767], while BMI less than 18.5 kg/m2 (OR 2.921, 95% CI 1.030–8.280, P = 0.044) was a risk factor associated with unfavorable outcomes (Table S1).
Safety
In the DM group, 83 patients (77.6%) reported a total of 170 AEs within the 24-week intensive treatment period. The most commonly reported AEs were ECG abnormalities (44.9%), hepatotoxicity (i.e., liver enzyme abnormalities) (38.3%), renal injury (12.1%), hematological injury (11.2%), and gastrointestinal symptoms response (10.3%).
In the non-DM group, 69 patients (64.5%) reported a total of 126 AEs during the 24-week intensive treatment course. The most commonly reported AEs in this group were ECG abnormalities (45.8%), hepatotoxicity (16.8%), peripheral neuropathy (13.1%), hematological injury (11.2%), and renal injury (7.5%). Other AEs and proportions of patients experiencing them are shown in Table 5. Except for hepatotoxicity, peripheral neuropathy, and headache and dizziness, no significant intergroup differences in adverse event rates were reported and no deaths occurred.Table 5 Frequency of adverse events reported in two groups
Adverse event, no. (%) DM group (n = 107) Non-DM group (n = 107) P value
Electrocardiogram abnormality 48 (44.9) 49 (45.8) 0.891
QTcF abnormalities 42 (39.3) 43 (40.2)
Othersa 6 (5.6) 6 (5.6)
Hepatotoxicity 41 (38.3) 18 (16.8) < 0.001
Renal injury 13 (12.1) 8 (7.5) 0.251
Optic neuritis 7 (6.5) 6 (5.6) 0.775
Ototoxicity 4 (3.7) 6 (5.6) 0.746
Hematological injury 12 (11.2) 12 (11.2) > 0.999
Gastrointestinal symptoms response 11 (10.3) 4 (3.7) 0.108
Peripheral neuropathy 4 (3.7) 14 (13.1) 0.027
Dermatologic reaction 0 (0) 2 (1.9) 0.498
Arthralgia 3 (2.8) 0 (0) 0.246
Hemoptysis 5 (4.7) 2 (1.9) 0.442
Psychiatric symptoms 6 (5.6) 3 (2.8) 0.496
Electrolyte disturbance 4 (3.7) 1 (0.9) 0.369
Headache and dizziness 6 (5.6) 0 (0) 0.029
Fever 2 (1.9) 0 (0) 0.498
Othersb 4 (3.7) 1 (0.9) 0.369
aIncluding arrhythmias, T wave changes
bIn the DM group, it included syncope, cerebral infarction, upper respiratory tract infection, and thyroid dysfunction; in the non-DM group, it included intestinal obstruction
Table 6 presents QTcF profiles of the two groups. The mean baseline QTcF of patients with MDR/XDR-TB and DM was 412.1 ms (SD = 22.4), which is higher than that of patients without DM (P = 0.021). The mean QTcF of both groups increased during the 24-week treatment with the aforementioned BDQ-containing anti-TB regimen, with significant intergroup differences observed (P = 0.005).Table 6 QTcF profiles in two groups
QTcF, ms DM group (n = 107) Non-DM group (n = 107) P value
Mean baseline QTcF (SD) 412.1 ± 22.4 404.6 ± 24.7 0.021
Mean QTcF during treatment (SD) 424.9 ± 28.3 420.7 ± 28.6 0.005
Patients with at least one QTcF greater than 450 ms, no. (%) 42 (39.3) 43 (40.2) 0.889
Patients with at least one QTcF increment from baseline greater than 60 ms, no. (%) 15 (14.0) 20 (18.7) 0.355
Patients with at least one QTcF greater than 500 ms, no. (%) 4 (3.7) 4 (3.7) > 0.999
QTcF QT interval with Fridericia correction
Numbers of patients with DM and at least one QTcF ≥ 500 ms or one increment of QTcF ≥ 60 ms from baseline were 4 (3.7%) and 15 (14%), respectively, with corresponding numbers of patients without DM of 4 (3.7%) and 20 (18.7%) observed and no significant intergroup differences observed (DM: P > 0.999; non-DM: P = 0.355). For the eight patients whose QTcF values reached the critical threshold of 500 ms, ECG and electrolyte measurements were repeated and four patients with DM continued BDQ administration with normal electrolyte levels and QTcF values (less than 500 ms) were observed when repeated; meanwhile, one in four of these patients without DM permanently discontinued BDQ, due to persistently high QTcF levels noted after repeated ECG monitoring and confirmation.
Discussion
Findings of previous studies suggested that DM may undermine the absorption, distribution, biotransformation, and excretion of many pharmaceutical agents [15]. Given bedaquiline’s unique pharmacokinetic profile [16], its pharmacokinetics in patients with DM may be altered by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy, and also by possible drug–drug interactions with hypoglycemic agents [17]. Although BDQ has been used to treat MDR/XDR-TB for years, few studies related to efficacy and safety of BDQ-containing anti-TB regimens administered to patients with DM have been reported, prompting us to conduct this first study to date to investigate this topic.
In this respective cohort study, 16.7% of patients with MDR/XDR-TB had DM, mirroring DM/DR-TB rates reported in South Korea [6]. In the African region, the most common MDR/XDR-TB comorbidity is HIV, while in the Western Pacific region, DM is a more common comorbidity in this patient group. Such findings have influenced policy making and implementation measures by regional or national TB Programs (NTP). In order to maintain consistency of key intergroup baseline characteristics, here a control without DM was matched with a comparable patient with DM for each social demographic factor (age and sex) and DST profile in a 1:1 ratio between groups. Mirroring observations reported in other studies [18], patients with MDR/XDR-TB and DM were more likely to exhibit baseline clinical signs associated with greater disease severity (e.g., positive bacteriological status, lung cavities). Here we also found that patients with MDR/XDR-TB with lower BMIs (less than 18.5 kg/m2) tended to have unfavorable treatment outcomes (OR 2.291, 95% CI 1.030–8.280, P = 0.044), mirroring findings reported by our team earlier this year [19]. Meanwhile, no significant statistical intergroup differences were observed for baseline characteristics of other anti-TB drugs used to formulate optimal background regimens. Although baseline DM group disease severity exceeded that of the group of patients without DM, no significant intergroup differences were observed in median time to culture conversion (56 days, IQR 28–63 days vs. 56 days, IQR 28–84 days, P = 0.876) or culture conversion rates (80.0% vs. 81.4%, P = 0.844) at 8 weeks and (95.6% vs. 98.2%, P = 0.629) at 24 weeks of anti-TB treatment. Notably, the aforementioned median time to culture conversion results found here mirrored results reported by Salhotra et al. [20] and Borisov et al. [21], while the 24-week culture conversion rate found here exceeded the 6-month culture conversion rate reported in a South Korean study (80%, n = 21) [22] and the rate of 78% (n = 537) reported in a multinational study (France, Georgia, Armenia, South Africa) [23].
It is widely accepted that metformin and insulin analogues used to control high blood glucose levels also possess anti-inflammatory properties that render these hypoglycemic agents useful for treating severe infections, such as MDR/XDR-TB with comorbid DM [17]. Indeed, the inclusion of insulin and metformin or both agents in treatment regimens for the vast majority of patients with DM has likely already benefited patients afflicted with both MDR/XDR-TB and DM. Nevertheless, findings of this study suggest that even in patients with MDR/XDR-TB and DM who receive hypoglycemic agent-based treatments, favorable treatment outcomes (e.g., rapid time to culture conversion results, optimal culture conversion rates) are still attainable with 24-week-long intensive anti-TB treatment with BDQ-containing regimens.
Many AEs experienced during MDR/XDR-TB treatment have been attributed to comorbid DM [24]. Since BDQ increased all-cause mortality rates of patients with MDR/XDR-TB in a phase IIb trial, BDQ toxicity has always been a major concern, especially for patients with MDR/XDR-TB and DM. Here we also found that patients with MDR/XDR-TB and DM reported AEs more frequently than did their non-DM counterparts, with most frequently observed AEs in both groups of ECG abnormalities and hepatotoxicity. With regard to ECG abnormalities, mean baseline QTcF and mean QTcF values of MDR/XDR-TB DM group patients during the 24-week treatment course were higher than respective non-DM group values, although no significant differences from baseline between groups were noted in occurrence of QTcF ≥ 500 ms or increment of QTcF ≥ 60 ms.
BDQ is metabolized primarily through hepatic metabolic pathways that are shared with several oral hypoglycemic agents (e.g., thiazolidinedione, acarbose); thus, hepatic-related adverse reactions may develop more frequently when BDQ and hypoglycemic agents are used together [17]. Consequently, here 38.3% of patients with MDR/XDR-TB and DM reported incidents of hepatotoxicity manifesting primarily as liver enzyme (AST/ALT) elevations, significantly more than the non-DM group rate (16.8%) (P < 0.001). Even though occurrences of AEs, such as peripheral neuropathy, headache, and dizziness, were more commonly reported by patients with DM, most of these AEs were of grade 1 or 2 in severity, with few grade 3 or 4 AEs and no grade 5 AEs observed in either group as evidence for safety and tolerability of BDQ-containing regimens when administered to both groups.
In 2015, the WHO released its active TB drug safety monitoring and management (aDSM) framework, which described how to implement active pharmacovigilance in order to quickly detect, manage, and report suspected or confirmed drug toxicities within the context of new drugs and short treatment regimens. The first global report for surveillance of adverse event of 26 countries recently demonstrated that aDSM was feasible and the overall proportion of AEs was reasonably low (8.7% of patients with serious AEs (grade 3 and 4, no grade 5 AEs) with treatment regimens including BDQ and delamanid (DLM) [25]. aDSM was implemented since NDIP initiated in China and provided valuable information on the AEs in Chinese patients treated with new and repurposed anti-TB drugs, including the subpopulations with DM in this study.
Recently, the role of BDQ and/or DLM in patients with DR-TB and comorbidities such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) coinfection, or DM have been reported. Olayanju et al. found that there were no significant differences in 6-month culture conversion and 18-month favorable outcome rate in the BDQ versus BDQ-DLM combination group in HIV-infected patients. Furthermore, the BDQ-DLM combination regimen presented comparable long-term safety to BDQ-based regimen in patients with DR-TB irrespective of HIV status [26]. Franke et al., on behalf of the endTB observational study team, reported culture conversion of patients with MDR-TB with BDQ and/or DLM, from 17 epidemiologically diverse countries with comorbidities such as HIV, HCV, or diabetes. Patients with HIV had lower probability of conversion than patients without HIV. Patients with HCV or DM/glucose intolerance were not associated with culture conversion [27].
This study had several limitations. First, as inherent to all retrospective studies, DM diagnosis was based on medical records since we were unable to track patient fasting glucose levels and glycosylated hemoglobin data monthly to assess effects of glycemic control measures on treatment outcomes. Second, we assessed initial TB severity based on pulmonary imaging findings for patients in both groups at baseline but were unable to assess pulmonary cavity closure at 24 weeks, hindering our evaluation of treatment results. Third, we focused on interim outcomes at 24 weeks rather than final outcomes based on sputum culture. Further studies are warranted to determine final treatment outcomes and relapse rates in this cohort. Finally, despite few reported culture reversion, short-term follow-up may lead to overestimation of culture conversion rates.
Conclusion
This study demonstrated that patients with MDR/XDR-TB and DM were more likely than patients without DM to exhibit clinically greater disease severity at baseline. Nevertheless, patients with MDR/XDR-TB with and without DM undergoing treatment with BDQ-containing regimens achieved equally satisfactory sputum culture conversion rates with acceptable safety and drug tolerability observed for all patients after 24 weeks of treatment.
Supplementary Information
Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)
Acknowledgements
We expressed our thanks to Long Jin, Ming Wang, Pengfei Ren, Qi Qi, Chunmei Hu, Qiuping Wu, Mei Lin, Huailong Jiang, Na Yang, Saiduo Liu, Dan Yi, Dan Cui, Yuqing Wu, and Linchun Wu for their time and efforts in patients’ follow-up and data collection. We also acknowledge the outstanding contributions from the Clinical Center on Tuberculosis, China CDC and all workers of the NDIP program.
Funding
This work was supported by Science and Technology Bureau Project of Changsha (grant number 2018-kq1801145); Hunan Administration of Traditional Chinese Medicine (grant number 201890) and Scientific Research Project of Hunan Provincial Health Commission (grant number 20201439) , the journal’s Rapid Service was supported by NDIP project.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authors’ Contributions
LS, JG, MG, YL, PD, SC, MH, and YP contributed to the study conception and design. Patient management and data collection were performed by WF, XY, YH, FH, YH, LL, XL, XH, ZL, PT, JH, HW, JD, and YH, and statistical analysis was performed by LS, WS, and YS. The first draft of the manuscript was written by LS and JG. MG, YL, and YP commented on previous versions of the manuscript. All authors read and approved the final manuscript. LS, JG, and MG are the co-first authors and contributed equally to this study.
Disclosures
Li Shi, Jingtao Gao, Mengqiu Gao, Ping Deng, Shu Chen, Minfu He, Wenjun Feng, Xiaoyun Yang, Yunhui Huang, Fang He, Yumeng Hu, Liping Lei, Xuelian Li, Juan Du, Xiaomeng Hu, Zhi Liu, Peijun Tang, Junfeng Han, Hua Wang, Yi Han, Wei Shu, Yuxian Sun, Yi Pei, and Yuhong Liu have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study protocol was approved by the ethics committee of each participating hospital. Beijing Chest Hospital is the leader of the study with reference number of (No. 5 of 2018). The study was also approved by the ethics committees of the following hospitals: Changsha Central Hospital affiliated to University of South China, Chest Hospital of Jiangxi Province, Anhui Chest Hospital, Tianjin Haihe Hospital, Wuhan Pulmonary Hospital, The Fifth People’s Hospital of Suzhou, The Third People's Hospital of Shenzhen, Guiyang Public Health Center, Fuzhou Pulmonary Hospital, Guangzhou Chest Hospital, Wenzhou Central Hospital, Heilongjiang Tuberculosis Prevention and Control Institute, Qingdao Chest Hospital, Jilin Tuberculosis Prevention and Control Institute, Hangzhou Red Cross Hospital, Shenyang Chest Hospital, Hainan Second People's Hospital, Nanjing Second People's Hospital, The Sixth People's Hospital of Zhengzhou and Hebei Chest Hospital. Each patient provided their informed consent before they were enrolled into NDIP.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Jingtao Gao and Mengqiu Gao are the co-first authors for this article. | Oral | DrugAdministrationRoute | CC BY-NC | 33515206 | 18,875,374 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bacterial sepsis'. | Abatacept as salvage therapy in chronic graft-versus-host disease-a retrospective analysis.
The immunomodulatory fusion protein abatacept has recently been investigated for the treatment of steroid-refractory chronic graft-versus-host disease (cGvHD) in a phase 1 clinical trial. We analyzed the safety and efficacy of abatacept for cGvHD therapy in a retrospective study with 15 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received abatacept for cGvHD with a median age of 49 years. Grading was performed as part of the clinical routine according to the National Institute of Health's (NIH) consensus criteria at initiation of abatacept and 1, 3, 6, 9 and 12 months thereafter. The median time of follow-up was 191 days (range 55-393 days). Best overall response rate (ORR) was 40%. In particular, patients with bronchiolitis obliterans syndrome showed significant clinical improvement and durable responses following abatacept treatment with a response rate of 89% based on improvement in lung severity score (n = 6) or stabilized lung function (n = 4) or both (n = 3). Infectious complications CTCAE °III or higher were observed in 3/15 patients. None of the patients relapsed from the underlying malignancy. Thus, abatacept appears to be a promising treatment option for cGvHD, in particular for patients with lung involvement. However, further evaluation within a phase 2 clinical trial is required.
Introduction
While allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established, potentially curative therapy for several malignant and benign hematologic diseases, chronic graft-versus-host disease (cGvHD) remains a major complication after allo-HSCT. cGvHD occurs in up to 70% of patients after allo-HSCT and significantly contributes to impaired quality of life and non-relapse mortality (NRM)/transplant-related mortality (TRM) [1–5].
Corticosteroids represent the backbone of cGVHD treatment, but contribute to an already high morbidity and mortality by causing complications such as osteoporosis, myopathy, avascular necrosis, and glaucoma [3, 6]. A substantial number of patients does not respond to corticosteroids alone and require second-line therapy with the recently FDA-approved Bruton’s tyrosine kinase inhibitor ibrutinib or extracorporeal photopheresis [5, 7–9]. Further treatment options are usually based on retrospective or phase 1/2 clinical studies and show limited efficacy in a significant proportion of patients despite harboring the risk of toxicity including infectious complications [10–14].
Abatacept is a novel, first in class immunomodulatory drug exerting its effect by costimulatory blockade and is applied for the treatment of rheumatoid arthritis and other rheumatological diseases [15–17]. It is a recombinant fusion protein comprised of the extracellular domain of the immune checkpoint protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4) fused to the Fc fragment of IgG1 [18]. By binding with high affinity to the costimulatory receptors CD80 and CD86 on antigen presenting cells (APCs), it counteracts the costimulatory signal mediated by the ligand CD28, which is required for full T cell activation [19].
The highly complex pathophysiology of cGvHD is still poorly understood. Apart from alloreactive donor T cell responses, it involves aberrant innate immune signaling, endothelial cell injury, dysfunctional central tolerance induction (due to thymic damage as a result of the conditioning regimen or alloreactive T cells), insufficient de novo development of regulatory T cells (Treg), dysregulation of B cells, and cytokine signaling eventually resulting in chronic inflammation and fibrotic remodeling [20–22].
Since cGvHD is at least in part mediated by host reactive T cells stimulated by allogeneic antigens [23], there is high rationale for abatacept as a treatment option in cGvHD, and it has been reported that CTLA-4 blockade can prevent aGvHD and cGvHD and even reverse cGvHD in murine models [24]. Recently, abatacept has received breakthrough approval by the American Food and Drug Administration (FDA) for the prevention of acute GvHD and has shown efficacy in a phase 1 clinical trial for patients with steroid-refractory cGvHD, albeit with relatively low patient numbers [25].
Therefore, we analyzed the efficacy and safety of abatacept for the treatment of advanced cGvHD in a multicentric retrospective study.
Patients and methods
Patients
In this retrospective analysis, patients treated with abatacept for cGvHD between 2018 and 2020 at the University Hospital Regensburg (Germany), University Hospital Giessen and Marburg (Germany), University Hospital and Karolinska Institutet (Stockholm, Sweden) and University Hospital La Paz (Madrid, Spain) were included into the analysis approved by the institutional ethics review board (no.19-1586-104). Documentation of cGvHD was performed as part of clinical routine using the diagnosis and response criteria according to the National Institute of Health (NIH) consensus guidelines [26]. No new immunosuppressive agent was applied within at least 4 weeks before abatacept therapy, and response assessment was discontinued upon requirement of any additional immunosuppressive treatment post abatacept therapy. Patients received abatacept intravenously at a dose of 10 mg/kg body weight (maximum 800 mg) every 2 weeks for the first three doses and then every 4 weeks.
Definition of abatacept response and adverse events
Response to abatacept was assessed at 1, 3, 6, 9, and 12 months after start of therapy. In case of treatment with an additional immunosuppressive agent, the last response assessment for abatacept was performed at onset of new therapy. Last follow-up of the present analysis was January 2020. Complete remission (CR) was defined as resolution of all organ manifestations of cGvHD. Improvement of at least one organ grade without progression of cGvHD at other organs was classified as partial response (PR); mixed response was defined as simultaneous improvement in one organ and progression in another organ. Patients who showed no change in organ grading were classified as stable disease (SD). Failure-free survival (FFS) was defined as absence of relapse or non-relapse mortality or addition of further systemic therapy. Overall response rates (ORR) were calculated based on intention to treat analysis. Infectious complications were assessed and classified according to the common terminology criteria for adverse events version 5.0 (CTCAE 5.0) with toxicities captured in the analysis starting from grade III.
Results
Patient characteristics
We treated 15 patients with abatacept for cGvHD at our centers between 2018 and 2020. Among those patients, the diagnoses leading to allo-HSCT were myeloid disorders (acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasia (MPN)) in 10 patients, lymphatic malignancies (acute lymphoblastic leukemia (ALL), and Hodgkin lymphoma (HL)) in four patients and one patient suffering from CTLA-4 haploinsufficiency.
All patients had received peripheral blood stem cells (PBSC) as graft source with 11 patients grafted from an HLA-matched sibling (5 patients) or an unrelated donor (8 patients). HLA-matched donors were defined as 10/10 match. One patient had received an HLA-C mismatched graft from an unrelated donor, and one patient received a haploidentical graft from a related donor. Acute GvHD grade II or higher according to Glucksberg criteria occurred in 11 patients (85%). cGvHD onset was quiescent in 8 patients, de novo in three patients and progressive in four patients. Most of the patients (n = 12; 80%), who received abatacept, had severe cGvHD. One patient included in the analysis had mild cGvHD (prior history of moderate cGvHD) and received abatacept due to intolerance to other immunosuppressive agents. One patient was treated for autoimmune-hemolytic anemia (AIHA) refractory to corticosteroids and rituximab not fulfilling the NIH criteria for cGvHD falling in the category “undefined other cGvHD” [26, 27]. The majority of the patients had steroid dependent cGvHD (n = 10, 67%, all others steroid-refractory cGvHD (n = 5; 33%)). A platelet count < 100/nl was observed in 4 patients (27%) at the time of abatacept initiation.
The most common organ manifestations of cGvHD were skin (n = 11; 73%), lung (n = 11; 73%), eyes (n = 10; 67%), and oral cavity (n = 10; 67%). Abatacept was initiated on median day 1848 (range 432–7953) after allo-HSCT and on day 1592 (range 28–7864) after cGvHD onset, respectively. The corticosteroid dose at abatacept initiation was 0.34 mg/kg in median (range 0,12–2 mg/kg). The patients included in the analysis had received a median of 4.6 prior treatment lines (range 2–5) for cGvHD. Within 3 months before abatacept treatment was started, most patients did not undergo new immunosuppressive treatments (80%). The remaining patients (20%), who underwent new immunosuppressive treatments within 3 months, were progressive or refractory to the initiated treatment.
Median follow-up after treatment was 179 days (range 55–393). Patient characteristics including age, gender, diagnosis, donor type, stem cell source, conditioning regimen, GvHD prophylaxis, history of acute GvHD, and chronic GvHD are shown in Table 1.Table 1 Patient characteristics
Patient characteristics Value
Patients 15
Female, n (%) 10
Male, n (%) 5
Age, median (range)* 49 (5–70)
Diagnosis
AML, n (%) 7 (47)
ALL, n (%) 2 (13)
MPN (%) 3 (15)
Others, n (%) 3 (15)
Donor type
HLA-matched unrelated, n (%) 7 (47)
HLA-mismatched unrelated, n (%) 1 (7)
HLA-matched related, n (%) 6 (40)
HLA-mismatched related, n (%) 0
Haploidentical related, n (%) 1 (7)
Sex mismatch: female to male
Yes, n (%) 1 (7)
No, n (%) 14 (93)
Stem cell source
Peripheral blood stem cells, n (%) 14 (93)
Bone marrow, n (%) 1 (7)
GvHD prophylaxis
ATG/CsA/MTX, n (%) 3 (20)
CsA/MTX, n (%) 5 (33)
CsA/MMF, n (%) 1 (7)
Other 6 (40)
History of aGvHD
Grades 0–I, n (%) 4 (27)
Grades II–IV, n (%) 11 (73)
Characteristics Value
Onset of cGvHD after allo-SCT, median days (range) 256 (76–597)
Time point of abatacept treatment after allo-SCT, median days, (range) 1848 (432–7953)
Time point of abatacept treatment after cGvHD onset, median days, (range) 1592 (133–7864)
Age at abatacept initiation, median (range) 49 (5–70)
Number of abatacept doses, median (range) 7.1 (1–20)
cGvHD, n (%)
Mild 1 (7)
Moderate 0
Severe
non-NIH defined (AIHA)
13 (87)
1 (7)
Steroid response of cGvHD
Steroid resistance 5 (33)
Steroid dependence 10 (67)
Number of organ involvement of cGvHD, n (%)
One 1 (7)
Two 1 (7)
Three 5 (33)
Four or more 8 (53)
Type of cGvHD organ involvement, n (%)
Skin 11 (73)
Oral 10 (67)
Eyes 10 (67)
Liver 2 (13)
Gut 4 (27)
Lung 11 (73)
Musculoskeletal 7 (47)
Genital 2 (13)
AIHA 1 (7)
ISM at the beginning of abatacept, n (%)
No ISM 0
One ISM 5 (33)
Two ISM 8 (53)
Three or more ISM 2 (13)
Number of prior therapies before abatacept, n (%)
One 2 (13)
Two 2 13)
Three 1 (7)
Four or more prior therapies 10 (67)
New ISM within 3 months before abatacept, n (%)
Yes 3 (20)
No 12 (80)
n number of patients, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, MPN myeloproliferative neoplasia, HLA human leukocyte antigen, ATG anti-thymocyte globulin, CsA ciclosporin A, MTX methotrexate, MMF mycophenolate mofetil, GvHD graft-versus-host disease, aGvHD acute GvHD, cGvHD chronic GvHD, ISM immunosuppressive medication
Response to abatacept
Response to abatacept treatment is illustrated in Fig. 1 and Table 2 at the different time points of this analysis.Fig. 1 Clinical course during abatacept treatment
Table 2 Duration of abatacept treatment and clinical course
Patient # Day of start IS at start # of doses Organ involvement (grade) at start Skin features at start 1 m RR 2 m RR 3 m RR 6 m RR 9 m RR 12 m RR Follow up
1 7953 GC, E, MMF 7 s (0), e (3), m (0), f (0), lu (3) - SD SD SD SD - - Stabilized lung function, abatacept discontinued due to prolonged fatigue and diarrhea after administration
2 1596 GC, Rux 6 s (3), e (1), m (1), f (2), lu (2) S PR PR PR - - - Improvement of lung GvHD, new IS with ibrutinib and tocilizumab after 6 months
3 3261 GC, CsA 2 s (3), e (0), m (2), f (2), lu (0) S SD SD SD SD - - New IS with daratumumab after no improvement of oral ulcers
4 1425 GC 4 s (3), e (1), m (1), f (2), lu (2) S SD MR SD - - - Death due to aortic valve rupture (preexisting aortic valve insufficiency)
5 949 GC, Rux 3 s (3), e (2), m (0), f (2), lu (0) S SD SD - - - - New IS with Treg after 2 months
6 722 GC 10 s (0), e (3), m (0), f (0), lu (3) - PR PR PR PR - - Stabilized lung GvHD and improved functional capacity, death due to sepsis 9 months after abatacept start
7 1318 GC 1 s (0), e (0), m (1), f (0), lu (0) - PR PR - - - - Abatacept was given due to intolerance to IS agents and multiple infectious complications; death due to infectious complications of PAD
8 4587 GC, Bari 5 s (3), e (0), m (0), f (2), lu (0) S SD SD SD - - - New IS with tofacitinib after persisting arthralgia
9* 1311 GC, Ima 14 s (1), e (1), m (1), gi (1), f (0), lu (3) L PR PR PR PR PR PR Durable improvement of lung and skin GvHD. Less oxygen demand, reduced coughing
10* 432 GC, E 14 s (3), e (1), m (1), f (0), lu (0) S SD SD PR PR PR PR Improvement of ocular GvHD
11 1162 GC, Tac 9 s (1), e (3), m (1), f (0), lu (3) L MR MR MR MR - - Stabilized lung function, progressive oral affection, new IS with ruxolitinib after 9 months
12* 517 Toc 13 s (2), m (1), gi (1), li (1), f (0), lu (3) L PR PR PR PR PR PR Complete resolution of s, m, gi and li GvHD. Significant improvement of lung GvHD (reduction from grades 3 to 1)
13* 157 GC 4 AIHA - CR CR CR CR NR NR Complete resolution of AIHA
14* 469 GC, Ibru s (0), e (0), m (1), gi (0), f (0), lu (1) - SD SD SD NR NR NR Stabilized lung function
15* 1864 CsA 10 s (1), e (1), m (2), gi (0), f (2), lu (3) L SD PR PR PR PR NR Increased mobility and improved lung symptoms
Median 1848 7
1/3/6/9/12-month RR 1/3/6/12-month response rate, respectively; GC glucocorticoid; E everolimus; MMF mycophenolate mofetil; Rux ruxolitinib; CsA cyclosporine A; Bari baricitinib; Ima imatinib; Tac tacrolimus; Toc tocilizumab; Ibru ibrutinib; s skin; e eyes; m mouth; f fascia; lu lungs; ge genital; S sclerotic features; L lichen planus-like features; PD progressive disease; SD stable disease; PR partial response; MR mixed response; NR not reached; Treg regulatory T cells; IS immunosuppression; PAD peripheral artery disease; QOL quality of life; AIHA autoimmune hemolytic anemia; *ongoing therapy
Response to abatacept at 1 month
One month after first administration of abatacept, the patient (7%) with AIHA showed CR, 5 (33%) patients had PR, one patient (7%) showed MR with improved lung function but progressive oral affection, and 8 patients (53%) presented with SD. None of the patients required start of an additional immunosuppressive therapy. The overall response rate (ORR) at 1 month was 40%, and failure-free survival (FFS) was 100%.
Response to abatacept at 3 months
At 3 months after start of abatacept therapy, one patient showed CR (7%), 5 (33%) patients had PR, one patient showed MR (7%), and 6 patients (40%) had SD. One patient who had SD started a new immunosuppression and another patient with a PR succumbed to infectious complications of severe peripheral artery disease unrelated to abatacept. ORR at 3 months was therefore 40% with an FFS of 87%.
Response to abatacept at 6 and 9 months
The 6 months follow-up was reached by nine patients with one patient remaining in CR (7%), four patients achieving PR (27%), one MR (7%) with sustained stabilized lung function but impaired oral affection, and two patients with SD (13%). At termination of our analysis, one patient was still treated with abatacept but has not reached the 6 months follow-up yet. One patient with PR started a new IS with ibrutinib and tocilizumab, and another patient who was in SD discontinued abatacept and was switched to tofacitinib due to persisting arthralgia. One highly comorbid patient with preexisting aortic valve insufficiency died due to aortic valve rupture. Thus, the ORR at 6 months was 33% with an FFS of 64%.
Nine months after initiation of abatacept treatment, four patients still received therapy and two patients currently still receiving abatacept have not reached the time point yet. Of the remaining patients, three showed a PR (20%), one patient discontinued abatacept due to sustained and not improved oral ulcers, and another patient died due to urosepsis, displaying an ORR of 23% with an FFS of 31%.
Response to abatacept at 12 months
At 12 months, three patients were still treated with abatacept, and three who currently receive abatacept therapy have not reached the time point yet. Three patients still had PR (25%) resulting in an ORR of 25% with FFS of 25%.
Response in patients with lung involvement of cGvHD
Interestingly, we observed that patients with lung involvement (n = 9) particularly benefitted from therapy with abatacept with an overall response rate of 89% based on improvement in lung severity score (n = 6), lung function as measured by FEV1 in Fig. 1 (n = 4) or both (n = 3). Of note, although only a stabilization on abatacept was achieved, they experienced prior constant loss of FEV1 as shown in Fig. 1. Of note, all patients received in parallel therapy with FAM (fluticasone, azithromycine, montelukast) partly in combination with beta-agonists which had already been applied > 1 month before abatacept initiation without response (Fig. 2).Fig. 2 Forced expiratory volume % before and during abatacept therapy
Infectious and other complications during abatacept
Adverse events (AE) and serious adverse events (SAE) during abatacept treatment are illustrated in Table 3. In general, abatacept administration was well tolerated; however, one patient repeatedly showed nausea, vomiting, diarrhea, fever, and fatigue for several days repeatedly upon infusion leading to termination of treatment after 7 applications. Another patient showed alopecia during treatment. Three of the patients included in the analysis developed significant infectious complications requiring hospital admission with one highly comorbid patient succumbing to urosepsis, and another patient already mentioned died due to infectious complications associated with severe peripheral artery disease unrelated to cGvHD.Table 3 Adverse and serious adverse events of abatacept treatment
Patient # AE SAE Specification
1 Yes No Fatigue, diarrhea, fever
2 No Yes Death due to gram-negative sepsis 70 days after last abatacept dose
3 No No -
4 No No -
5 No No -
6 No Yes Death due to urosepsis 24 days after last abatacept dose
7 No Yes Death due to infectious complications of peripheral artery disease
8 No No -
9 No No -
10 Yes No Alopecia after abatacept initiation
11 No No -
12 No Yes Hospital admission due to influenza A pneumonia
13 No No -
14 No No -
15 Yes No Bone pain after infusion
Discussion
cGvHD occurs with an incidence of 30–70% in patients undergoing allo-HSCT [21], and as it reduces quality of life and significantly contributes to NRM/TRM, there is still a high clinical need for effective second-line treatments [28, 29]. The underlying complex pathophysiology of cGvHD involves both B and T cell immunity and results in pleiotropic clinical manifestations resembling various autoimmune diseases [21]. Due to the involvement of auto- und alloreactive T cells in the development and course of cGvHD, there is high rationale for the use of costimulation blockade via the CTLA-4 pathway [20]. The introduction of the immunomodulatory drug abatacept has significantly improved the therapy for rheumatoid arthritis patients not responding sufficiently to conventional disease modifying antirheumatic drugs and has in this context shown efficacy and improvement of quality of life [19, 30, 31]. Based on observations in preclinical models, abatacept has been tested in combination with a CD25 monoclonal antibody in pediatric recipients of haploidentical allo-HSCT for the treatment of hyperacute GvHD, where it has shown efficacy [32]. Moreover, the safety and efficacy of abatacept for the prevention of aGvHD and treatment of SR-cGvHD were recently evaluated with promising results in phase 1 clinical trials [25, 33], and subsequent randomized phase 2 trials have been initiated (NCT0174313; NCT01954979).
In this retrospective analysis of cGvHD patients treated with abatacept at four centers, we observed a best overall response rate of 40%, which is comparable to the clinical response rate of 44% recently reported by Nahas et al. [25]. Despite the low number of patients and the retrospective character of the analysis, we observed that in particular patients with bronchiolitis obliterans syndrome (BOS) showed substantial clinical improvement after abatacept application with durable responses, stabilized lung function (Fig. 1), albeit this was not reflected by an improvement in lung grading in all patients. Given the frequently irreversible character of lung involvement due to fibrotic remodeling, we consider clinical improvement, lowering of oxygen demand, and stabilized lung function as relevant response parameters, especially in our patient cohort with mostly severe cGVHD [34]. Interestingly, it has been reported for several autoimmune diseases that costimulation blockade of the CTLA-4 axis selectively decreases the proportion of T follicular helper cells, thereby reducing T cell help for germinal center B cells [35–37]. Given that BOS is explicitly characterized by disturbance of B cell homeostasis with increased CD19+CD21- B cells and excess of B cell activation factor (BAFF) [38], abatacept might target Tfh cells in this context, which would at least partially explain the particular improvement of patients with BOS in our study. In addition, we observed a complete response in a steroid and rituximab refractory AIHA patient as previously described [39]. Despite not meeting NIH diagnostic criteria for cGvHD, we included this patient in our analysis since it has recently been reported that based on biomarker profiles, patients with signs of immune mediated damage not diagnostic for cGvHD do not significantly differ from those showing diagnostic signs of cGvHD suggesting that the current NIH diagnostic criteria may not involve all targets of cGvHD [40, 41]. Noteworthy, in the phase 1 clinical trial reported by Nahas et al., a reduction of corticosteroid usage of 51.3% was reported, while the authors state that this effect might have been overestimated due to the not blinded or randomized design of the study. In this regard, we did not observe consistent steroid reduction in patients responding to abatacept, yet most of our patients received a relatively low corticosteroid dose at start of abatacept. Interestingly, it has been reported in a preclinical model of chronic lung allograft dysfunction that bronchiolitis obliterans can be attenuated by CTLA-4-Ig administration presumably by promoting LAG3+Treg mediated anti-inflammatory effects providing a potential mechanistic explanation for the observed clinical response [42]. Of note, progression of cGvHD within three months was indicative for treatment failure, and all patients, who achieved at least a PR, were responding in the first three months. Thus, based on our experience, we would suggest discontinuing abatacept treatment, if patients do not show a response within this period. Overall, abatacept seems to be a relevant treatment option for patients with cGvHD, particularly for patients with BOS, but this has to be further investigated in future clinical trials.
Funding
Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projekt-ID 324392634 - TRR221, subproject B10 (D.W.), and by the ReForM program of the University of Regensburg (T.W.).
Declarations
Conflict of interest
D. W. received honoraria from Mallinckrodt, Novartis, Takeda, MACO, and Neovii.
The authors declare that they have no conflict of interest.
Informed consent
Informed consent was obtained from all patients for being included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Matthias Fante and Daniel Wolff contributed equally to this work. | ABATACEPT | DrugsGivenReaction | CC BY | 33515310 | 18,904,824 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infection'. | Abatacept as salvage therapy in chronic graft-versus-host disease-a retrospective analysis.
The immunomodulatory fusion protein abatacept has recently been investigated for the treatment of steroid-refractory chronic graft-versus-host disease (cGvHD) in a phase 1 clinical trial. We analyzed the safety and efficacy of abatacept for cGvHD therapy in a retrospective study with 15 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received abatacept for cGvHD with a median age of 49 years. Grading was performed as part of the clinical routine according to the National Institute of Health's (NIH) consensus criteria at initiation of abatacept and 1, 3, 6, 9 and 12 months thereafter. The median time of follow-up was 191 days (range 55-393 days). Best overall response rate (ORR) was 40%. In particular, patients with bronchiolitis obliterans syndrome showed significant clinical improvement and durable responses following abatacept treatment with a response rate of 89% based on improvement in lung severity score (n = 6) or stabilized lung function (n = 4) or both (n = 3). Infectious complications CTCAE °III or higher were observed in 3/15 patients. None of the patients relapsed from the underlying malignancy. Thus, abatacept appears to be a promising treatment option for cGvHD, in particular for patients with lung involvement. However, further evaluation within a phase 2 clinical trial is required.
Introduction
While allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established, potentially curative therapy for several malignant and benign hematologic diseases, chronic graft-versus-host disease (cGvHD) remains a major complication after allo-HSCT. cGvHD occurs in up to 70% of patients after allo-HSCT and significantly contributes to impaired quality of life and non-relapse mortality (NRM)/transplant-related mortality (TRM) [1–5].
Corticosteroids represent the backbone of cGVHD treatment, but contribute to an already high morbidity and mortality by causing complications such as osteoporosis, myopathy, avascular necrosis, and glaucoma [3, 6]. A substantial number of patients does not respond to corticosteroids alone and require second-line therapy with the recently FDA-approved Bruton’s tyrosine kinase inhibitor ibrutinib or extracorporeal photopheresis [5, 7–9]. Further treatment options are usually based on retrospective or phase 1/2 clinical studies and show limited efficacy in a significant proportion of patients despite harboring the risk of toxicity including infectious complications [10–14].
Abatacept is a novel, first in class immunomodulatory drug exerting its effect by costimulatory blockade and is applied for the treatment of rheumatoid arthritis and other rheumatological diseases [15–17]. It is a recombinant fusion protein comprised of the extracellular domain of the immune checkpoint protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4) fused to the Fc fragment of IgG1 [18]. By binding with high affinity to the costimulatory receptors CD80 and CD86 on antigen presenting cells (APCs), it counteracts the costimulatory signal mediated by the ligand CD28, which is required for full T cell activation [19].
The highly complex pathophysiology of cGvHD is still poorly understood. Apart from alloreactive donor T cell responses, it involves aberrant innate immune signaling, endothelial cell injury, dysfunctional central tolerance induction (due to thymic damage as a result of the conditioning regimen or alloreactive T cells), insufficient de novo development of regulatory T cells (Treg), dysregulation of B cells, and cytokine signaling eventually resulting in chronic inflammation and fibrotic remodeling [20–22].
Since cGvHD is at least in part mediated by host reactive T cells stimulated by allogeneic antigens [23], there is high rationale for abatacept as a treatment option in cGvHD, and it has been reported that CTLA-4 blockade can prevent aGvHD and cGvHD and even reverse cGvHD in murine models [24]. Recently, abatacept has received breakthrough approval by the American Food and Drug Administration (FDA) for the prevention of acute GvHD and has shown efficacy in a phase 1 clinical trial for patients with steroid-refractory cGvHD, albeit with relatively low patient numbers [25].
Therefore, we analyzed the efficacy and safety of abatacept for the treatment of advanced cGvHD in a multicentric retrospective study.
Patients and methods
Patients
In this retrospective analysis, patients treated with abatacept for cGvHD between 2018 and 2020 at the University Hospital Regensburg (Germany), University Hospital Giessen and Marburg (Germany), University Hospital and Karolinska Institutet (Stockholm, Sweden) and University Hospital La Paz (Madrid, Spain) were included into the analysis approved by the institutional ethics review board (no.19-1586-104). Documentation of cGvHD was performed as part of clinical routine using the diagnosis and response criteria according to the National Institute of Health (NIH) consensus guidelines [26]. No new immunosuppressive agent was applied within at least 4 weeks before abatacept therapy, and response assessment was discontinued upon requirement of any additional immunosuppressive treatment post abatacept therapy. Patients received abatacept intravenously at a dose of 10 mg/kg body weight (maximum 800 mg) every 2 weeks for the first three doses and then every 4 weeks.
Definition of abatacept response and adverse events
Response to abatacept was assessed at 1, 3, 6, 9, and 12 months after start of therapy. In case of treatment with an additional immunosuppressive agent, the last response assessment for abatacept was performed at onset of new therapy. Last follow-up of the present analysis was January 2020. Complete remission (CR) was defined as resolution of all organ manifestations of cGvHD. Improvement of at least one organ grade without progression of cGvHD at other organs was classified as partial response (PR); mixed response was defined as simultaneous improvement in one organ and progression in another organ. Patients who showed no change in organ grading were classified as stable disease (SD). Failure-free survival (FFS) was defined as absence of relapse or non-relapse mortality or addition of further systemic therapy. Overall response rates (ORR) were calculated based on intention to treat analysis. Infectious complications were assessed and classified according to the common terminology criteria for adverse events version 5.0 (CTCAE 5.0) with toxicities captured in the analysis starting from grade III.
Results
Patient characteristics
We treated 15 patients with abatacept for cGvHD at our centers between 2018 and 2020. Among those patients, the diagnoses leading to allo-HSCT were myeloid disorders (acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasia (MPN)) in 10 patients, lymphatic malignancies (acute lymphoblastic leukemia (ALL), and Hodgkin lymphoma (HL)) in four patients and one patient suffering from CTLA-4 haploinsufficiency.
All patients had received peripheral blood stem cells (PBSC) as graft source with 11 patients grafted from an HLA-matched sibling (5 patients) or an unrelated donor (8 patients). HLA-matched donors were defined as 10/10 match. One patient had received an HLA-C mismatched graft from an unrelated donor, and one patient received a haploidentical graft from a related donor. Acute GvHD grade II or higher according to Glucksberg criteria occurred in 11 patients (85%). cGvHD onset was quiescent in 8 patients, de novo in three patients and progressive in four patients. Most of the patients (n = 12; 80%), who received abatacept, had severe cGvHD. One patient included in the analysis had mild cGvHD (prior history of moderate cGvHD) and received abatacept due to intolerance to other immunosuppressive agents. One patient was treated for autoimmune-hemolytic anemia (AIHA) refractory to corticosteroids and rituximab not fulfilling the NIH criteria for cGvHD falling in the category “undefined other cGvHD” [26, 27]. The majority of the patients had steroid dependent cGvHD (n = 10, 67%, all others steroid-refractory cGvHD (n = 5; 33%)). A platelet count < 100/nl was observed in 4 patients (27%) at the time of abatacept initiation.
The most common organ manifestations of cGvHD were skin (n = 11; 73%), lung (n = 11; 73%), eyes (n = 10; 67%), and oral cavity (n = 10; 67%). Abatacept was initiated on median day 1848 (range 432–7953) after allo-HSCT and on day 1592 (range 28–7864) after cGvHD onset, respectively. The corticosteroid dose at abatacept initiation was 0.34 mg/kg in median (range 0,12–2 mg/kg). The patients included in the analysis had received a median of 4.6 prior treatment lines (range 2–5) for cGvHD. Within 3 months before abatacept treatment was started, most patients did not undergo new immunosuppressive treatments (80%). The remaining patients (20%), who underwent new immunosuppressive treatments within 3 months, were progressive or refractory to the initiated treatment.
Median follow-up after treatment was 179 days (range 55–393). Patient characteristics including age, gender, diagnosis, donor type, stem cell source, conditioning regimen, GvHD prophylaxis, history of acute GvHD, and chronic GvHD are shown in Table 1.Table 1 Patient characteristics
Patient characteristics Value
Patients 15
Female, n (%) 10
Male, n (%) 5
Age, median (range)* 49 (5–70)
Diagnosis
AML, n (%) 7 (47)
ALL, n (%) 2 (13)
MPN (%) 3 (15)
Others, n (%) 3 (15)
Donor type
HLA-matched unrelated, n (%) 7 (47)
HLA-mismatched unrelated, n (%) 1 (7)
HLA-matched related, n (%) 6 (40)
HLA-mismatched related, n (%) 0
Haploidentical related, n (%) 1 (7)
Sex mismatch: female to male
Yes, n (%) 1 (7)
No, n (%) 14 (93)
Stem cell source
Peripheral blood stem cells, n (%) 14 (93)
Bone marrow, n (%) 1 (7)
GvHD prophylaxis
ATG/CsA/MTX, n (%) 3 (20)
CsA/MTX, n (%) 5 (33)
CsA/MMF, n (%) 1 (7)
Other 6 (40)
History of aGvHD
Grades 0–I, n (%) 4 (27)
Grades II–IV, n (%) 11 (73)
Characteristics Value
Onset of cGvHD after allo-SCT, median days (range) 256 (76–597)
Time point of abatacept treatment after allo-SCT, median days, (range) 1848 (432–7953)
Time point of abatacept treatment after cGvHD onset, median days, (range) 1592 (133–7864)
Age at abatacept initiation, median (range) 49 (5–70)
Number of abatacept doses, median (range) 7.1 (1–20)
cGvHD, n (%)
Mild 1 (7)
Moderate 0
Severe
non-NIH defined (AIHA)
13 (87)
1 (7)
Steroid response of cGvHD
Steroid resistance 5 (33)
Steroid dependence 10 (67)
Number of organ involvement of cGvHD, n (%)
One 1 (7)
Two 1 (7)
Three 5 (33)
Four or more 8 (53)
Type of cGvHD organ involvement, n (%)
Skin 11 (73)
Oral 10 (67)
Eyes 10 (67)
Liver 2 (13)
Gut 4 (27)
Lung 11 (73)
Musculoskeletal 7 (47)
Genital 2 (13)
AIHA 1 (7)
ISM at the beginning of abatacept, n (%)
No ISM 0
One ISM 5 (33)
Two ISM 8 (53)
Three or more ISM 2 (13)
Number of prior therapies before abatacept, n (%)
One 2 (13)
Two 2 13)
Three 1 (7)
Four or more prior therapies 10 (67)
New ISM within 3 months before abatacept, n (%)
Yes 3 (20)
No 12 (80)
n number of patients, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, MPN myeloproliferative neoplasia, HLA human leukocyte antigen, ATG anti-thymocyte globulin, CsA ciclosporin A, MTX methotrexate, MMF mycophenolate mofetil, GvHD graft-versus-host disease, aGvHD acute GvHD, cGvHD chronic GvHD, ISM immunosuppressive medication
Response to abatacept
Response to abatacept treatment is illustrated in Fig. 1 and Table 2 at the different time points of this analysis.Fig. 1 Clinical course during abatacept treatment
Table 2 Duration of abatacept treatment and clinical course
Patient # Day of start IS at start # of doses Organ involvement (grade) at start Skin features at start 1 m RR 2 m RR 3 m RR 6 m RR 9 m RR 12 m RR Follow up
1 7953 GC, E, MMF 7 s (0), e (3), m (0), f (0), lu (3) - SD SD SD SD - - Stabilized lung function, abatacept discontinued due to prolonged fatigue and diarrhea after administration
2 1596 GC, Rux 6 s (3), e (1), m (1), f (2), lu (2) S PR PR PR - - - Improvement of lung GvHD, new IS with ibrutinib and tocilizumab after 6 months
3 3261 GC, CsA 2 s (3), e (0), m (2), f (2), lu (0) S SD SD SD SD - - New IS with daratumumab after no improvement of oral ulcers
4 1425 GC 4 s (3), e (1), m (1), f (2), lu (2) S SD MR SD - - - Death due to aortic valve rupture (preexisting aortic valve insufficiency)
5 949 GC, Rux 3 s (3), e (2), m (0), f (2), lu (0) S SD SD - - - - New IS with Treg after 2 months
6 722 GC 10 s (0), e (3), m (0), f (0), lu (3) - PR PR PR PR - - Stabilized lung GvHD and improved functional capacity, death due to sepsis 9 months after abatacept start
7 1318 GC 1 s (0), e (0), m (1), f (0), lu (0) - PR PR - - - - Abatacept was given due to intolerance to IS agents and multiple infectious complications; death due to infectious complications of PAD
8 4587 GC, Bari 5 s (3), e (0), m (0), f (2), lu (0) S SD SD SD - - - New IS with tofacitinib after persisting arthralgia
9* 1311 GC, Ima 14 s (1), e (1), m (1), gi (1), f (0), lu (3) L PR PR PR PR PR PR Durable improvement of lung and skin GvHD. Less oxygen demand, reduced coughing
10* 432 GC, E 14 s (3), e (1), m (1), f (0), lu (0) S SD SD PR PR PR PR Improvement of ocular GvHD
11 1162 GC, Tac 9 s (1), e (3), m (1), f (0), lu (3) L MR MR MR MR - - Stabilized lung function, progressive oral affection, new IS with ruxolitinib after 9 months
12* 517 Toc 13 s (2), m (1), gi (1), li (1), f (0), lu (3) L PR PR PR PR PR PR Complete resolution of s, m, gi and li GvHD. Significant improvement of lung GvHD (reduction from grades 3 to 1)
13* 157 GC 4 AIHA - CR CR CR CR NR NR Complete resolution of AIHA
14* 469 GC, Ibru s (0), e (0), m (1), gi (0), f (0), lu (1) - SD SD SD NR NR NR Stabilized lung function
15* 1864 CsA 10 s (1), e (1), m (2), gi (0), f (2), lu (3) L SD PR PR PR PR NR Increased mobility and improved lung symptoms
Median 1848 7
1/3/6/9/12-month RR 1/3/6/12-month response rate, respectively; GC glucocorticoid; E everolimus; MMF mycophenolate mofetil; Rux ruxolitinib; CsA cyclosporine A; Bari baricitinib; Ima imatinib; Tac tacrolimus; Toc tocilizumab; Ibru ibrutinib; s skin; e eyes; m mouth; f fascia; lu lungs; ge genital; S sclerotic features; L lichen planus-like features; PD progressive disease; SD stable disease; PR partial response; MR mixed response; NR not reached; Treg regulatory T cells; IS immunosuppression; PAD peripheral artery disease; QOL quality of life; AIHA autoimmune hemolytic anemia; *ongoing therapy
Response to abatacept at 1 month
One month after first administration of abatacept, the patient (7%) with AIHA showed CR, 5 (33%) patients had PR, one patient (7%) showed MR with improved lung function but progressive oral affection, and 8 patients (53%) presented with SD. None of the patients required start of an additional immunosuppressive therapy. The overall response rate (ORR) at 1 month was 40%, and failure-free survival (FFS) was 100%.
Response to abatacept at 3 months
At 3 months after start of abatacept therapy, one patient showed CR (7%), 5 (33%) patients had PR, one patient showed MR (7%), and 6 patients (40%) had SD. One patient who had SD started a new immunosuppression and another patient with a PR succumbed to infectious complications of severe peripheral artery disease unrelated to abatacept. ORR at 3 months was therefore 40% with an FFS of 87%.
Response to abatacept at 6 and 9 months
The 6 months follow-up was reached by nine patients with one patient remaining in CR (7%), four patients achieving PR (27%), one MR (7%) with sustained stabilized lung function but impaired oral affection, and two patients with SD (13%). At termination of our analysis, one patient was still treated with abatacept but has not reached the 6 months follow-up yet. One patient with PR started a new IS with ibrutinib and tocilizumab, and another patient who was in SD discontinued abatacept and was switched to tofacitinib due to persisting arthralgia. One highly comorbid patient with preexisting aortic valve insufficiency died due to aortic valve rupture. Thus, the ORR at 6 months was 33% with an FFS of 64%.
Nine months after initiation of abatacept treatment, four patients still received therapy and two patients currently still receiving abatacept have not reached the time point yet. Of the remaining patients, three showed a PR (20%), one patient discontinued abatacept due to sustained and not improved oral ulcers, and another patient died due to urosepsis, displaying an ORR of 23% with an FFS of 31%.
Response to abatacept at 12 months
At 12 months, three patients were still treated with abatacept, and three who currently receive abatacept therapy have not reached the time point yet. Three patients still had PR (25%) resulting in an ORR of 25% with FFS of 25%.
Response in patients with lung involvement of cGvHD
Interestingly, we observed that patients with lung involvement (n = 9) particularly benefitted from therapy with abatacept with an overall response rate of 89% based on improvement in lung severity score (n = 6), lung function as measured by FEV1 in Fig. 1 (n = 4) or both (n = 3). Of note, although only a stabilization on abatacept was achieved, they experienced prior constant loss of FEV1 as shown in Fig. 1. Of note, all patients received in parallel therapy with FAM (fluticasone, azithromycine, montelukast) partly in combination with beta-agonists which had already been applied > 1 month before abatacept initiation without response (Fig. 2).Fig. 2 Forced expiratory volume % before and during abatacept therapy
Infectious and other complications during abatacept
Adverse events (AE) and serious adverse events (SAE) during abatacept treatment are illustrated in Table 3. In general, abatacept administration was well tolerated; however, one patient repeatedly showed nausea, vomiting, diarrhea, fever, and fatigue for several days repeatedly upon infusion leading to termination of treatment after 7 applications. Another patient showed alopecia during treatment. Three of the patients included in the analysis developed significant infectious complications requiring hospital admission with one highly comorbid patient succumbing to urosepsis, and another patient already mentioned died due to infectious complications associated with severe peripheral artery disease unrelated to cGvHD.Table 3 Adverse and serious adverse events of abatacept treatment
Patient # AE SAE Specification
1 Yes No Fatigue, diarrhea, fever
2 No Yes Death due to gram-negative sepsis 70 days after last abatacept dose
3 No No -
4 No No -
5 No No -
6 No Yes Death due to urosepsis 24 days after last abatacept dose
7 No Yes Death due to infectious complications of peripheral artery disease
8 No No -
9 No No -
10 Yes No Alopecia after abatacept initiation
11 No No -
12 No Yes Hospital admission due to influenza A pneumonia
13 No No -
14 No No -
15 Yes No Bone pain after infusion
Discussion
cGvHD occurs with an incidence of 30–70% in patients undergoing allo-HSCT [21], and as it reduces quality of life and significantly contributes to NRM/TRM, there is still a high clinical need for effective second-line treatments [28, 29]. The underlying complex pathophysiology of cGvHD involves both B and T cell immunity and results in pleiotropic clinical manifestations resembling various autoimmune diseases [21]. Due to the involvement of auto- und alloreactive T cells in the development and course of cGvHD, there is high rationale for the use of costimulation blockade via the CTLA-4 pathway [20]. The introduction of the immunomodulatory drug abatacept has significantly improved the therapy for rheumatoid arthritis patients not responding sufficiently to conventional disease modifying antirheumatic drugs and has in this context shown efficacy and improvement of quality of life [19, 30, 31]. Based on observations in preclinical models, abatacept has been tested in combination with a CD25 monoclonal antibody in pediatric recipients of haploidentical allo-HSCT for the treatment of hyperacute GvHD, where it has shown efficacy [32]. Moreover, the safety and efficacy of abatacept for the prevention of aGvHD and treatment of SR-cGvHD were recently evaluated with promising results in phase 1 clinical trials [25, 33], and subsequent randomized phase 2 trials have been initiated (NCT0174313; NCT01954979).
In this retrospective analysis of cGvHD patients treated with abatacept at four centers, we observed a best overall response rate of 40%, which is comparable to the clinical response rate of 44% recently reported by Nahas et al. [25]. Despite the low number of patients and the retrospective character of the analysis, we observed that in particular patients with bronchiolitis obliterans syndrome (BOS) showed substantial clinical improvement after abatacept application with durable responses, stabilized lung function (Fig. 1), albeit this was not reflected by an improvement in lung grading in all patients. Given the frequently irreversible character of lung involvement due to fibrotic remodeling, we consider clinical improvement, lowering of oxygen demand, and stabilized lung function as relevant response parameters, especially in our patient cohort with mostly severe cGVHD [34]. Interestingly, it has been reported for several autoimmune diseases that costimulation blockade of the CTLA-4 axis selectively decreases the proportion of T follicular helper cells, thereby reducing T cell help for germinal center B cells [35–37]. Given that BOS is explicitly characterized by disturbance of B cell homeostasis with increased CD19+CD21- B cells and excess of B cell activation factor (BAFF) [38], abatacept might target Tfh cells in this context, which would at least partially explain the particular improvement of patients with BOS in our study. In addition, we observed a complete response in a steroid and rituximab refractory AIHA patient as previously described [39]. Despite not meeting NIH diagnostic criteria for cGvHD, we included this patient in our analysis since it has recently been reported that based on biomarker profiles, patients with signs of immune mediated damage not diagnostic for cGvHD do not significantly differ from those showing diagnostic signs of cGvHD suggesting that the current NIH diagnostic criteria may not involve all targets of cGvHD [40, 41]. Noteworthy, in the phase 1 clinical trial reported by Nahas et al., a reduction of corticosteroid usage of 51.3% was reported, while the authors state that this effect might have been overestimated due to the not blinded or randomized design of the study. In this regard, we did not observe consistent steroid reduction in patients responding to abatacept, yet most of our patients received a relatively low corticosteroid dose at start of abatacept. Interestingly, it has been reported in a preclinical model of chronic lung allograft dysfunction that bronchiolitis obliterans can be attenuated by CTLA-4-Ig administration presumably by promoting LAG3+Treg mediated anti-inflammatory effects providing a potential mechanistic explanation for the observed clinical response [42]. Of note, progression of cGvHD within three months was indicative for treatment failure, and all patients, who achieved at least a PR, were responding in the first three months. Thus, based on our experience, we would suggest discontinuing abatacept treatment, if patients do not show a response within this period. Overall, abatacept seems to be a relevant treatment option for patients with cGvHD, particularly for patients with BOS, but this has to be further investigated in future clinical trials.
Funding
Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projekt-ID 324392634 - TRR221, subproject B10 (D.W.), and by the ReForM program of the University of Regensburg (T.W.).
Declarations
Conflict of interest
D. W. received honoraria from Mallinckrodt, Novartis, Takeda, MACO, and Neovii.
The authors declare that they have no conflict of interest.
Informed consent
Informed consent was obtained from all patients for being included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Matthias Fante and Daniel Wolff contributed equally to this work. | ABATACEPT | DrugsGivenReaction | CC BY | 33515310 | 18,904,556 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intentional product use issue'. | Abatacept as salvage therapy in chronic graft-versus-host disease-a retrospective analysis.
The immunomodulatory fusion protein abatacept has recently been investigated for the treatment of steroid-refractory chronic graft-versus-host disease (cGvHD) in a phase 1 clinical trial. We analyzed the safety and efficacy of abatacept for cGvHD therapy in a retrospective study with 15 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received abatacept for cGvHD with a median age of 49 years. Grading was performed as part of the clinical routine according to the National Institute of Health's (NIH) consensus criteria at initiation of abatacept and 1, 3, 6, 9 and 12 months thereafter. The median time of follow-up was 191 days (range 55-393 days). Best overall response rate (ORR) was 40%. In particular, patients with bronchiolitis obliterans syndrome showed significant clinical improvement and durable responses following abatacept treatment with a response rate of 89% based on improvement in lung severity score (n = 6) or stabilized lung function (n = 4) or both (n = 3). Infectious complications CTCAE °III or higher were observed in 3/15 patients. None of the patients relapsed from the underlying malignancy. Thus, abatacept appears to be a promising treatment option for cGvHD, in particular for patients with lung involvement. However, further evaluation within a phase 2 clinical trial is required.
Introduction
While allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established, potentially curative therapy for several malignant and benign hematologic diseases, chronic graft-versus-host disease (cGvHD) remains a major complication after allo-HSCT. cGvHD occurs in up to 70% of patients after allo-HSCT and significantly contributes to impaired quality of life and non-relapse mortality (NRM)/transplant-related mortality (TRM) [1–5].
Corticosteroids represent the backbone of cGVHD treatment, but contribute to an already high morbidity and mortality by causing complications such as osteoporosis, myopathy, avascular necrosis, and glaucoma [3, 6]. A substantial number of patients does not respond to corticosteroids alone and require second-line therapy with the recently FDA-approved Bruton’s tyrosine kinase inhibitor ibrutinib or extracorporeal photopheresis [5, 7–9]. Further treatment options are usually based on retrospective or phase 1/2 clinical studies and show limited efficacy in a significant proportion of patients despite harboring the risk of toxicity including infectious complications [10–14].
Abatacept is a novel, first in class immunomodulatory drug exerting its effect by costimulatory blockade and is applied for the treatment of rheumatoid arthritis and other rheumatological diseases [15–17]. It is a recombinant fusion protein comprised of the extracellular domain of the immune checkpoint protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4) fused to the Fc fragment of IgG1 [18]. By binding with high affinity to the costimulatory receptors CD80 and CD86 on antigen presenting cells (APCs), it counteracts the costimulatory signal mediated by the ligand CD28, which is required for full T cell activation [19].
The highly complex pathophysiology of cGvHD is still poorly understood. Apart from alloreactive donor T cell responses, it involves aberrant innate immune signaling, endothelial cell injury, dysfunctional central tolerance induction (due to thymic damage as a result of the conditioning regimen or alloreactive T cells), insufficient de novo development of regulatory T cells (Treg), dysregulation of B cells, and cytokine signaling eventually resulting in chronic inflammation and fibrotic remodeling [20–22].
Since cGvHD is at least in part mediated by host reactive T cells stimulated by allogeneic antigens [23], there is high rationale for abatacept as a treatment option in cGvHD, and it has been reported that CTLA-4 blockade can prevent aGvHD and cGvHD and even reverse cGvHD in murine models [24]. Recently, abatacept has received breakthrough approval by the American Food and Drug Administration (FDA) for the prevention of acute GvHD and has shown efficacy in a phase 1 clinical trial for patients with steroid-refractory cGvHD, albeit with relatively low patient numbers [25].
Therefore, we analyzed the efficacy and safety of abatacept for the treatment of advanced cGvHD in a multicentric retrospective study.
Patients and methods
Patients
In this retrospective analysis, patients treated with abatacept for cGvHD between 2018 and 2020 at the University Hospital Regensburg (Germany), University Hospital Giessen and Marburg (Germany), University Hospital and Karolinska Institutet (Stockholm, Sweden) and University Hospital La Paz (Madrid, Spain) were included into the analysis approved by the institutional ethics review board (no.19-1586-104). Documentation of cGvHD was performed as part of clinical routine using the diagnosis and response criteria according to the National Institute of Health (NIH) consensus guidelines [26]. No new immunosuppressive agent was applied within at least 4 weeks before abatacept therapy, and response assessment was discontinued upon requirement of any additional immunosuppressive treatment post abatacept therapy. Patients received abatacept intravenously at a dose of 10 mg/kg body weight (maximum 800 mg) every 2 weeks for the first three doses and then every 4 weeks.
Definition of abatacept response and adverse events
Response to abatacept was assessed at 1, 3, 6, 9, and 12 months after start of therapy. In case of treatment with an additional immunosuppressive agent, the last response assessment for abatacept was performed at onset of new therapy. Last follow-up of the present analysis was January 2020. Complete remission (CR) was defined as resolution of all organ manifestations of cGvHD. Improvement of at least one organ grade without progression of cGvHD at other organs was classified as partial response (PR); mixed response was defined as simultaneous improvement in one organ and progression in another organ. Patients who showed no change in organ grading were classified as stable disease (SD). Failure-free survival (FFS) was defined as absence of relapse or non-relapse mortality or addition of further systemic therapy. Overall response rates (ORR) were calculated based on intention to treat analysis. Infectious complications were assessed and classified according to the common terminology criteria for adverse events version 5.0 (CTCAE 5.0) with toxicities captured in the analysis starting from grade III.
Results
Patient characteristics
We treated 15 patients with abatacept for cGvHD at our centers between 2018 and 2020. Among those patients, the diagnoses leading to allo-HSCT were myeloid disorders (acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasia (MPN)) in 10 patients, lymphatic malignancies (acute lymphoblastic leukemia (ALL), and Hodgkin lymphoma (HL)) in four patients and one patient suffering from CTLA-4 haploinsufficiency.
All patients had received peripheral blood stem cells (PBSC) as graft source with 11 patients grafted from an HLA-matched sibling (5 patients) or an unrelated donor (8 patients). HLA-matched donors were defined as 10/10 match. One patient had received an HLA-C mismatched graft from an unrelated donor, and one patient received a haploidentical graft from a related donor. Acute GvHD grade II or higher according to Glucksberg criteria occurred in 11 patients (85%). cGvHD onset was quiescent in 8 patients, de novo in three patients and progressive in four patients. Most of the patients (n = 12; 80%), who received abatacept, had severe cGvHD. One patient included in the analysis had mild cGvHD (prior history of moderate cGvHD) and received abatacept due to intolerance to other immunosuppressive agents. One patient was treated for autoimmune-hemolytic anemia (AIHA) refractory to corticosteroids and rituximab not fulfilling the NIH criteria for cGvHD falling in the category “undefined other cGvHD” [26, 27]. The majority of the patients had steroid dependent cGvHD (n = 10, 67%, all others steroid-refractory cGvHD (n = 5; 33%)). A platelet count < 100/nl was observed in 4 patients (27%) at the time of abatacept initiation.
The most common organ manifestations of cGvHD were skin (n = 11; 73%), lung (n = 11; 73%), eyes (n = 10; 67%), and oral cavity (n = 10; 67%). Abatacept was initiated on median day 1848 (range 432–7953) after allo-HSCT and on day 1592 (range 28–7864) after cGvHD onset, respectively. The corticosteroid dose at abatacept initiation was 0.34 mg/kg in median (range 0,12–2 mg/kg). The patients included in the analysis had received a median of 4.6 prior treatment lines (range 2–5) for cGvHD. Within 3 months before abatacept treatment was started, most patients did not undergo new immunosuppressive treatments (80%). The remaining patients (20%), who underwent new immunosuppressive treatments within 3 months, were progressive or refractory to the initiated treatment.
Median follow-up after treatment was 179 days (range 55–393). Patient characteristics including age, gender, diagnosis, donor type, stem cell source, conditioning regimen, GvHD prophylaxis, history of acute GvHD, and chronic GvHD are shown in Table 1.Table 1 Patient characteristics
Patient characteristics Value
Patients 15
Female, n (%) 10
Male, n (%) 5
Age, median (range)* 49 (5–70)
Diagnosis
AML, n (%) 7 (47)
ALL, n (%) 2 (13)
MPN (%) 3 (15)
Others, n (%) 3 (15)
Donor type
HLA-matched unrelated, n (%) 7 (47)
HLA-mismatched unrelated, n (%) 1 (7)
HLA-matched related, n (%) 6 (40)
HLA-mismatched related, n (%) 0
Haploidentical related, n (%) 1 (7)
Sex mismatch: female to male
Yes, n (%) 1 (7)
No, n (%) 14 (93)
Stem cell source
Peripheral blood stem cells, n (%) 14 (93)
Bone marrow, n (%) 1 (7)
GvHD prophylaxis
ATG/CsA/MTX, n (%) 3 (20)
CsA/MTX, n (%) 5 (33)
CsA/MMF, n (%) 1 (7)
Other 6 (40)
History of aGvHD
Grades 0–I, n (%) 4 (27)
Grades II–IV, n (%) 11 (73)
Characteristics Value
Onset of cGvHD after allo-SCT, median days (range) 256 (76–597)
Time point of abatacept treatment after allo-SCT, median days, (range) 1848 (432–7953)
Time point of abatacept treatment after cGvHD onset, median days, (range) 1592 (133–7864)
Age at abatacept initiation, median (range) 49 (5–70)
Number of abatacept doses, median (range) 7.1 (1–20)
cGvHD, n (%)
Mild 1 (7)
Moderate 0
Severe
non-NIH defined (AIHA)
13 (87)
1 (7)
Steroid response of cGvHD
Steroid resistance 5 (33)
Steroid dependence 10 (67)
Number of organ involvement of cGvHD, n (%)
One 1 (7)
Two 1 (7)
Three 5 (33)
Four or more 8 (53)
Type of cGvHD organ involvement, n (%)
Skin 11 (73)
Oral 10 (67)
Eyes 10 (67)
Liver 2 (13)
Gut 4 (27)
Lung 11 (73)
Musculoskeletal 7 (47)
Genital 2 (13)
AIHA 1 (7)
ISM at the beginning of abatacept, n (%)
No ISM 0
One ISM 5 (33)
Two ISM 8 (53)
Three or more ISM 2 (13)
Number of prior therapies before abatacept, n (%)
One 2 (13)
Two 2 13)
Three 1 (7)
Four or more prior therapies 10 (67)
New ISM within 3 months before abatacept, n (%)
Yes 3 (20)
No 12 (80)
n number of patients, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, MPN myeloproliferative neoplasia, HLA human leukocyte antigen, ATG anti-thymocyte globulin, CsA ciclosporin A, MTX methotrexate, MMF mycophenolate mofetil, GvHD graft-versus-host disease, aGvHD acute GvHD, cGvHD chronic GvHD, ISM immunosuppressive medication
Response to abatacept
Response to abatacept treatment is illustrated in Fig. 1 and Table 2 at the different time points of this analysis.Fig. 1 Clinical course during abatacept treatment
Table 2 Duration of abatacept treatment and clinical course
Patient # Day of start IS at start # of doses Organ involvement (grade) at start Skin features at start 1 m RR 2 m RR 3 m RR 6 m RR 9 m RR 12 m RR Follow up
1 7953 GC, E, MMF 7 s (0), e (3), m (0), f (0), lu (3) - SD SD SD SD - - Stabilized lung function, abatacept discontinued due to prolonged fatigue and diarrhea after administration
2 1596 GC, Rux 6 s (3), e (1), m (1), f (2), lu (2) S PR PR PR - - - Improvement of lung GvHD, new IS with ibrutinib and tocilizumab after 6 months
3 3261 GC, CsA 2 s (3), e (0), m (2), f (2), lu (0) S SD SD SD SD - - New IS with daratumumab after no improvement of oral ulcers
4 1425 GC 4 s (3), e (1), m (1), f (2), lu (2) S SD MR SD - - - Death due to aortic valve rupture (preexisting aortic valve insufficiency)
5 949 GC, Rux 3 s (3), e (2), m (0), f (2), lu (0) S SD SD - - - - New IS with Treg after 2 months
6 722 GC 10 s (0), e (3), m (0), f (0), lu (3) - PR PR PR PR - - Stabilized lung GvHD and improved functional capacity, death due to sepsis 9 months after abatacept start
7 1318 GC 1 s (0), e (0), m (1), f (0), lu (0) - PR PR - - - - Abatacept was given due to intolerance to IS agents and multiple infectious complications; death due to infectious complications of PAD
8 4587 GC, Bari 5 s (3), e (0), m (0), f (2), lu (0) S SD SD SD - - - New IS with tofacitinib after persisting arthralgia
9* 1311 GC, Ima 14 s (1), e (1), m (1), gi (1), f (0), lu (3) L PR PR PR PR PR PR Durable improvement of lung and skin GvHD. Less oxygen demand, reduced coughing
10* 432 GC, E 14 s (3), e (1), m (1), f (0), lu (0) S SD SD PR PR PR PR Improvement of ocular GvHD
11 1162 GC, Tac 9 s (1), e (3), m (1), f (0), lu (3) L MR MR MR MR - - Stabilized lung function, progressive oral affection, new IS with ruxolitinib after 9 months
12* 517 Toc 13 s (2), m (1), gi (1), li (1), f (0), lu (3) L PR PR PR PR PR PR Complete resolution of s, m, gi and li GvHD. Significant improvement of lung GvHD (reduction from grades 3 to 1)
13* 157 GC 4 AIHA - CR CR CR CR NR NR Complete resolution of AIHA
14* 469 GC, Ibru s (0), e (0), m (1), gi (0), f (0), lu (1) - SD SD SD NR NR NR Stabilized lung function
15* 1864 CsA 10 s (1), e (1), m (2), gi (0), f (2), lu (3) L SD PR PR PR PR NR Increased mobility and improved lung symptoms
Median 1848 7
1/3/6/9/12-month RR 1/3/6/12-month response rate, respectively; GC glucocorticoid; E everolimus; MMF mycophenolate mofetil; Rux ruxolitinib; CsA cyclosporine A; Bari baricitinib; Ima imatinib; Tac tacrolimus; Toc tocilizumab; Ibru ibrutinib; s skin; e eyes; m mouth; f fascia; lu lungs; ge genital; S sclerotic features; L lichen planus-like features; PD progressive disease; SD stable disease; PR partial response; MR mixed response; NR not reached; Treg regulatory T cells; IS immunosuppression; PAD peripheral artery disease; QOL quality of life; AIHA autoimmune hemolytic anemia; *ongoing therapy
Response to abatacept at 1 month
One month after first administration of abatacept, the patient (7%) with AIHA showed CR, 5 (33%) patients had PR, one patient (7%) showed MR with improved lung function but progressive oral affection, and 8 patients (53%) presented with SD. None of the patients required start of an additional immunosuppressive therapy. The overall response rate (ORR) at 1 month was 40%, and failure-free survival (FFS) was 100%.
Response to abatacept at 3 months
At 3 months after start of abatacept therapy, one patient showed CR (7%), 5 (33%) patients had PR, one patient showed MR (7%), and 6 patients (40%) had SD. One patient who had SD started a new immunosuppression and another patient with a PR succumbed to infectious complications of severe peripheral artery disease unrelated to abatacept. ORR at 3 months was therefore 40% with an FFS of 87%.
Response to abatacept at 6 and 9 months
The 6 months follow-up was reached by nine patients with one patient remaining in CR (7%), four patients achieving PR (27%), one MR (7%) with sustained stabilized lung function but impaired oral affection, and two patients with SD (13%). At termination of our analysis, one patient was still treated with abatacept but has not reached the 6 months follow-up yet. One patient with PR started a new IS with ibrutinib and tocilizumab, and another patient who was in SD discontinued abatacept and was switched to tofacitinib due to persisting arthralgia. One highly comorbid patient with preexisting aortic valve insufficiency died due to aortic valve rupture. Thus, the ORR at 6 months was 33% with an FFS of 64%.
Nine months after initiation of abatacept treatment, four patients still received therapy and two patients currently still receiving abatacept have not reached the time point yet. Of the remaining patients, three showed a PR (20%), one patient discontinued abatacept due to sustained and not improved oral ulcers, and another patient died due to urosepsis, displaying an ORR of 23% with an FFS of 31%.
Response to abatacept at 12 months
At 12 months, three patients were still treated with abatacept, and three who currently receive abatacept therapy have not reached the time point yet. Three patients still had PR (25%) resulting in an ORR of 25% with FFS of 25%.
Response in patients with lung involvement of cGvHD
Interestingly, we observed that patients with lung involvement (n = 9) particularly benefitted from therapy with abatacept with an overall response rate of 89% based on improvement in lung severity score (n = 6), lung function as measured by FEV1 in Fig. 1 (n = 4) or both (n = 3). Of note, although only a stabilization on abatacept was achieved, they experienced prior constant loss of FEV1 as shown in Fig. 1. Of note, all patients received in parallel therapy with FAM (fluticasone, azithromycine, montelukast) partly in combination with beta-agonists which had already been applied > 1 month before abatacept initiation without response (Fig. 2).Fig. 2 Forced expiratory volume % before and during abatacept therapy
Infectious and other complications during abatacept
Adverse events (AE) and serious adverse events (SAE) during abatacept treatment are illustrated in Table 3. In general, abatacept administration was well tolerated; however, one patient repeatedly showed nausea, vomiting, diarrhea, fever, and fatigue for several days repeatedly upon infusion leading to termination of treatment after 7 applications. Another patient showed alopecia during treatment. Three of the patients included in the analysis developed significant infectious complications requiring hospital admission with one highly comorbid patient succumbing to urosepsis, and another patient already mentioned died due to infectious complications associated with severe peripheral artery disease unrelated to cGvHD.Table 3 Adverse and serious adverse events of abatacept treatment
Patient # AE SAE Specification
1 Yes No Fatigue, diarrhea, fever
2 No Yes Death due to gram-negative sepsis 70 days after last abatacept dose
3 No No -
4 No No -
5 No No -
6 No Yes Death due to urosepsis 24 days after last abatacept dose
7 No Yes Death due to infectious complications of peripheral artery disease
8 No No -
9 No No -
10 Yes No Alopecia after abatacept initiation
11 No No -
12 No Yes Hospital admission due to influenza A pneumonia
13 No No -
14 No No -
15 Yes No Bone pain after infusion
Discussion
cGvHD occurs with an incidence of 30–70% in patients undergoing allo-HSCT [21], and as it reduces quality of life and significantly contributes to NRM/TRM, there is still a high clinical need for effective second-line treatments [28, 29]. The underlying complex pathophysiology of cGvHD involves both B and T cell immunity and results in pleiotropic clinical manifestations resembling various autoimmune diseases [21]. Due to the involvement of auto- und alloreactive T cells in the development and course of cGvHD, there is high rationale for the use of costimulation blockade via the CTLA-4 pathway [20]. The introduction of the immunomodulatory drug abatacept has significantly improved the therapy for rheumatoid arthritis patients not responding sufficiently to conventional disease modifying antirheumatic drugs and has in this context shown efficacy and improvement of quality of life [19, 30, 31]. Based on observations in preclinical models, abatacept has been tested in combination with a CD25 monoclonal antibody in pediatric recipients of haploidentical allo-HSCT for the treatment of hyperacute GvHD, where it has shown efficacy [32]. Moreover, the safety and efficacy of abatacept for the prevention of aGvHD and treatment of SR-cGvHD were recently evaluated with promising results in phase 1 clinical trials [25, 33], and subsequent randomized phase 2 trials have been initiated (NCT0174313; NCT01954979).
In this retrospective analysis of cGvHD patients treated with abatacept at four centers, we observed a best overall response rate of 40%, which is comparable to the clinical response rate of 44% recently reported by Nahas et al. [25]. Despite the low number of patients and the retrospective character of the analysis, we observed that in particular patients with bronchiolitis obliterans syndrome (BOS) showed substantial clinical improvement after abatacept application with durable responses, stabilized lung function (Fig. 1), albeit this was not reflected by an improvement in lung grading in all patients. Given the frequently irreversible character of lung involvement due to fibrotic remodeling, we consider clinical improvement, lowering of oxygen demand, and stabilized lung function as relevant response parameters, especially in our patient cohort with mostly severe cGVHD [34]. Interestingly, it has been reported for several autoimmune diseases that costimulation blockade of the CTLA-4 axis selectively decreases the proportion of T follicular helper cells, thereby reducing T cell help for germinal center B cells [35–37]. Given that BOS is explicitly characterized by disturbance of B cell homeostasis with increased CD19+CD21- B cells and excess of B cell activation factor (BAFF) [38], abatacept might target Tfh cells in this context, which would at least partially explain the particular improvement of patients with BOS in our study. In addition, we observed a complete response in a steroid and rituximab refractory AIHA patient as previously described [39]. Despite not meeting NIH diagnostic criteria for cGvHD, we included this patient in our analysis since it has recently been reported that based on biomarker profiles, patients with signs of immune mediated damage not diagnostic for cGvHD do not significantly differ from those showing diagnostic signs of cGvHD suggesting that the current NIH diagnostic criteria may not involve all targets of cGvHD [40, 41]. Noteworthy, in the phase 1 clinical trial reported by Nahas et al., a reduction of corticosteroid usage of 51.3% was reported, while the authors state that this effect might have been overestimated due to the not blinded or randomized design of the study. In this regard, we did not observe consistent steroid reduction in patients responding to abatacept, yet most of our patients received a relatively low corticosteroid dose at start of abatacept. Interestingly, it has been reported in a preclinical model of chronic lung allograft dysfunction that bronchiolitis obliterans can be attenuated by CTLA-4-Ig administration presumably by promoting LAG3+Treg mediated anti-inflammatory effects providing a potential mechanistic explanation for the observed clinical response [42]. Of note, progression of cGvHD within three months was indicative for treatment failure, and all patients, who achieved at least a PR, were responding in the first three months. Thus, based on our experience, we would suggest discontinuing abatacept treatment, if patients do not show a response within this period. Overall, abatacept seems to be a relevant treatment option for patients with cGvHD, particularly for patients with BOS, but this has to be further investigated in future clinical trials.
Funding
Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projekt-ID 324392634 - TRR221, subproject B10 (D.W.), and by the ReForM program of the University of Regensburg (T.W.).
Declarations
Conflict of interest
D. W. received honoraria from Mallinckrodt, Novartis, Takeda, MACO, and Neovii.
The authors declare that they have no conflict of interest.
Informed consent
Informed consent was obtained from all patients for being included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Matthias Fante and Daniel Wolff contributed equally to this work. | ABATACEPT | DrugsGivenReaction | CC BY | 33515310 | 18,904,824 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia influenzal'. | Abatacept as salvage therapy in chronic graft-versus-host disease-a retrospective analysis.
The immunomodulatory fusion protein abatacept has recently been investigated for the treatment of steroid-refractory chronic graft-versus-host disease (cGvHD) in a phase 1 clinical trial. We analyzed the safety and efficacy of abatacept for cGvHD therapy in a retrospective study with 15 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received abatacept for cGvHD with a median age of 49 years. Grading was performed as part of the clinical routine according to the National Institute of Health's (NIH) consensus criteria at initiation of abatacept and 1, 3, 6, 9 and 12 months thereafter. The median time of follow-up was 191 days (range 55-393 days). Best overall response rate (ORR) was 40%. In particular, patients with bronchiolitis obliterans syndrome showed significant clinical improvement and durable responses following abatacept treatment with a response rate of 89% based on improvement in lung severity score (n = 6) or stabilized lung function (n = 4) or both (n = 3). Infectious complications CTCAE °III or higher were observed in 3/15 patients. None of the patients relapsed from the underlying malignancy. Thus, abatacept appears to be a promising treatment option for cGvHD, in particular for patients with lung involvement. However, further evaluation within a phase 2 clinical trial is required.
Introduction
While allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established, potentially curative therapy for several malignant and benign hematologic diseases, chronic graft-versus-host disease (cGvHD) remains a major complication after allo-HSCT. cGvHD occurs in up to 70% of patients after allo-HSCT and significantly contributes to impaired quality of life and non-relapse mortality (NRM)/transplant-related mortality (TRM) [1–5].
Corticosteroids represent the backbone of cGVHD treatment, but contribute to an already high morbidity and mortality by causing complications such as osteoporosis, myopathy, avascular necrosis, and glaucoma [3, 6]. A substantial number of patients does not respond to corticosteroids alone and require second-line therapy with the recently FDA-approved Bruton’s tyrosine kinase inhibitor ibrutinib or extracorporeal photopheresis [5, 7–9]. Further treatment options are usually based on retrospective or phase 1/2 clinical studies and show limited efficacy in a significant proportion of patients despite harboring the risk of toxicity including infectious complications [10–14].
Abatacept is a novel, first in class immunomodulatory drug exerting its effect by costimulatory blockade and is applied for the treatment of rheumatoid arthritis and other rheumatological diseases [15–17]. It is a recombinant fusion protein comprised of the extracellular domain of the immune checkpoint protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4) fused to the Fc fragment of IgG1 [18]. By binding with high affinity to the costimulatory receptors CD80 and CD86 on antigen presenting cells (APCs), it counteracts the costimulatory signal mediated by the ligand CD28, which is required for full T cell activation [19].
The highly complex pathophysiology of cGvHD is still poorly understood. Apart from alloreactive donor T cell responses, it involves aberrant innate immune signaling, endothelial cell injury, dysfunctional central tolerance induction (due to thymic damage as a result of the conditioning regimen or alloreactive T cells), insufficient de novo development of regulatory T cells (Treg), dysregulation of B cells, and cytokine signaling eventually resulting in chronic inflammation and fibrotic remodeling [20–22].
Since cGvHD is at least in part mediated by host reactive T cells stimulated by allogeneic antigens [23], there is high rationale for abatacept as a treatment option in cGvHD, and it has been reported that CTLA-4 blockade can prevent aGvHD and cGvHD and even reverse cGvHD in murine models [24]. Recently, abatacept has received breakthrough approval by the American Food and Drug Administration (FDA) for the prevention of acute GvHD and has shown efficacy in a phase 1 clinical trial for patients with steroid-refractory cGvHD, albeit with relatively low patient numbers [25].
Therefore, we analyzed the efficacy and safety of abatacept for the treatment of advanced cGvHD in a multicentric retrospective study.
Patients and methods
Patients
In this retrospective analysis, patients treated with abatacept for cGvHD between 2018 and 2020 at the University Hospital Regensburg (Germany), University Hospital Giessen and Marburg (Germany), University Hospital and Karolinska Institutet (Stockholm, Sweden) and University Hospital La Paz (Madrid, Spain) were included into the analysis approved by the institutional ethics review board (no.19-1586-104). Documentation of cGvHD was performed as part of clinical routine using the diagnosis and response criteria according to the National Institute of Health (NIH) consensus guidelines [26]. No new immunosuppressive agent was applied within at least 4 weeks before abatacept therapy, and response assessment was discontinued upon requirement of any additional immunosuppressive treatment post abatacept therapy. Patients received abatacept intravenously at a dose of 10 mg/kg body weight (maximum 800 mg) every 2 weeks for the first three doses and then every 4 weeks.
Definition of abatacept response and adverse events
Response to abatacept was assessed at 1, 3, 6, 9, and 12 months after start of therapy. In case of treatment with an additional immunosuppressive agent, the last response assessment for abatacept was performed at onset of new therapy. Last follow-up of the present analysis was January 2020. Complete remission (CR) was defined as resolution of all organ manifestations of cGvHD. Improvement of at least one organ grade without progression of cGvHD at other organs was classified as partial response (PR); mixed response was defined as simultaneous improvement in one organ and progression in another organ. Patients who showed no change in organ grading were classified as stable disease (SD). Failure-free survival (FFS) was defined as absence of relapse or non-relapse mortality or addition of further systemic therapy. Overall response rates (ORR) were calculated based on intention to treat analysis. Infectious complications were assessed and classified according to the common terminology criteria for adverse events version 5.0 (CTCAE 5.0) with toxicities captured in the analysis starting from grade III.
Results
Patient characteristics
We treated 15 patients with abatacept for cGvHD at our centers between 2018 and 2020. Among those patients, the diagnoses leading to allo-HSCT were myeloid disorders (acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasia (MPN)) in 10 patients, lymphatic malignancies (acute lymphoblastic leukemia (ALL), and Hodgkin lymphoma (HL)) in four patients and one patient suffering from CTLA-4 haploinsufficiency.
All patients had received peripheral blood stem cells (PBSC) as graft source with 11 patients grafted from an HLA-matched sibling (5 patients) or an unrelated donor (8 patients). HLA-matched donors were defined as 10/10 match. One patient had received an HLA-C mismatched graft from an unrelated donor, and one patient received a haploidentical graft from a related donor. Acute GvHD grade II or higher according to Glucksberg criteria occurred in 11 patients (85%). cGvHD onset was quiescent in 8 patients, de novo in three patients and progressive in four patients. Most of the patients (n = 12; 80%), who received abatacept, had severe cGvHD. One patient included in the analysis had mild cGvHD (prior history of moderate cGvHD) and received abatacept due to intolerance to other immunosuppressive agents. One patient was treated for autoimmune-hemolytic anemia (AIHA) refractory to corticosteroids and rituximab not fulfilling the NIH criteria for cGvHD falling in the category “undefined other cGvHD” [26, 27]. The majority of the patients had steroid dependent cGvHD (n = 10, 67%, all others steroid-refractory cGvHD (n = 5; 33%)). A platelet count < 100/nl was observed in 4 patients (27%) at the time of abatacept initiation.
The most common organ manifestations of cGvHD were skin (n = 11; 73%), lung (n = 11; 73%), eyes (n = 10; 67%), and oral cavity (n = 10; 67%). Abatacept was initiated on median day 1848 (range 432–7953) after allo-HSCT and on day 1592 (range 28–7864) after cGvHD onset, respectively. The corticosteroid dose at abatacept initiation was 0.34 mg/kg in median (range 0,12–2 mg/kg). The patients included in the analysis had received a median of 4.6 prior treatment lines (range 2–5) for cGvHD. Within 3 months before abatacept treatment was started, most patients did not undergo new immunosuppressive treatments (80%). The remaining patients (20%), who underwent new immunosuppressive treatments within 3 months, were progressive or refractory to the initiated treatment.
Median follow-up after treatment was 179 days (range 55–393). Patient characteristics including age, gender, diagnosis, donor type, stem cell source, conditioning regimen, GvHD prophylaxis, history of acute GvHD, and chronic GvHD are shown in Table 1.Table 1 Patient characteristics
Patient characteristics Value
Patients 15
Female, n (%) 10
Male, n (%) 5
Age, median (range)* 49 (5–70)
Diagnosis
AML, n (%) 7 (47)
ALL, n (%) 2 (13)
MPN (%) 3 (15)
Others, n (%) 3 (15)
Donor type
HLA-matched unrelated, n (%) 7 (47)
HLA-mismatched unrelated, n (%) 1 (7)
HLA-matched related, n (%) 6 (40)
HLA-mismatched related, n (%) 0
Haploidentical related, n (%) 1 (7)
Sex mismatch: female to male
Yes, n (%) 1 (7)
No, n (%) 14 (93)
Stem cell source
Peripheral blood stem cells, n (%) 14 (93)
Bone marrow, n (%) 1 (7)
GvHD prophylaxis
ATG/CsA/MTX, n (%) 3 (20)
CsA/MTX, n (%) 5 (33)
CsA/MMF, n (%) 1 (7)
Other 6 (40)
History of aGvHD
Grades 0–I, n (%) 4 (27)
Grades II–IV, n (%) 11 (73)
Characteristics Value
Onset of cGvHD after allo-SCT, median days (range) 256 (76–597)
Time point of abatacept treatment after allo-SCT, median days, (range) 1848 (432–7953)
Time point of abatacept treatment after cGvHD onset, median days, (range) 1592 (133–7864)
Age at abatacept initiation, median (range) 49 (5–70)
Number of abatacept doses, median (range) 7.1 (1–20)
cGvHD, n (%)
Mild 1 (7)
Moderate 0
Severe
non-NIH defined (AIHA)
13 (87)
1 (7)
Steroid response of cGvHD
Steroid resistance 5 (33)
Steroid dependence 10 (67)
Number of organ involvement of cGvHD, n (%)
One 1 (7)
Two 1 (7)
Three 5 (33)
Four or more 8 (53)
Type of cGvHD organ involvement, n (%)
Skin 11 (73)
Oral 10 (67)
Eyes 10 (67)
Liver 2 (13)
Gut 4 (27)
Lung 11 (73)
Musculoskeletal 7 (47)
Genital 2 (13)
AIHA 1 (7)
ISM at the beginning of abatacept, n (%)
No ISM 0
One ISM 5 (33)
Two ISM 8 (53)
Three or more ISM 2 (13)
Number of prior therapies before abatacept, n (%)
One 2 (13)
Two 2 13)
Three 1 (7)
Four or more prior therapies 10 (67)
New ISM within 3 months before abatacept, n (%)
Yes 3 (20)
No 12 (80)
n number of patients, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, MPN myeloproliferative neoplasia, HLA human leukocyte antigen, ATG anti-thymocyte globulin, CsA ciclosporin A, MTX methotrexate, MMF mycophenolate mofetil, GvHD graft-versus-host disease, aGvHD acute GvHD, cGvHD chronic GvHD, ISM immunosuppressive medication
Response to abatacept
Response to abatacept treatment is illustrated in Fig. 1 and Table 2 at the different time points of this analysis.Fig. 1 Clinical course during abatacept treatment
Table 2 Duration of abatacept treatment and clinical course
Patient # Day of start IS at start # of doses Organ involvement (grade) at start Skin features at start 1 m RR 2 m RR 3 m RR 6 m RR 9 m RR 12 m RR Follow up
1 7953 GC, E, MMF 7 s (0), e (3), m (0), f (0), lu (3) - SD SD SD SD - - Stabilized lung function, abatacept discontinued due to prolonged fatigue and diarrhea after administration
2 1596 GC, Rux 6 s (3), e (1), m (1), f (2), lu (2) S PR PR PR - - - Improvement of lung GvHD, new IS with ibrutinib and tocilizumab after 6 months
3 3261 GC, CsA 2 s (3), e (0), m (2), f (2), lu (0) S SD SD SD SD - - New IS with daratumumab after no improvement of oral ulcers
4 1425 GC 4 s (3), e (1), m (1), f (2), lu (2) S SD MR SD - - - Death due to aortic valve rupture (preexisting aortic valve insufficiency)
5 949 GC, Rux 3 s (3), e (2), m (0), f (2), lu (0) S SD SD - - - - New IS with Treg after 2 months
6 722 GC 10 s (0), e (3), m (0), f (0), lu (3) - PR PR PR PR - - Stabilized lung GvHD and improved functional capacity, death due to sepsis 9 months after abatacept start
7 1318 GC 1 s (0), e (0), m (1), f (0), lu (0) - PR PR - - - - Abatacept was given due to intolerance to IS agents and multiple infectious complications; death due to infectious complications of PAD
8 4587 GC, Bari 5 s (3), e (0), m (0), f (2), lu (0) S SD SD SD - - - New IS with tofacitinib after persisting arthralgia
9* 1311 GC, Ima 14 s (1), e (1), m (1), gi (1), f (0), lu (3) L PR PR PR PR PR PR Durable improvement of lung and skin GvHD. Less oxygen demand, reduced coughing
10* 432 GC, E 14 s (3), e (1), m (1), f (0), lu (0) S SD SD PR PR PR PR Improvement of ocular GvHD
11 1162 GC, Tac 9 s (1), e (3), m (1), f (0), lu (3) L MR MR MR MR - - Stabilized lung function, progressive oral affection, new IS with ruxolitinib after 9 months
12* 517 Toc 13 s (2), m (1), gi (1), li (1), f (0), lu (3) L PR PR PR PR PR PR Complete resolution of s, m, gi and li GvHD. Significant improvement of lung GvHD (reduction from grades 3 to 1)
13* 157 GC 4 AIHA - CR CR CR CR NR NR Complete resolution of AIHA
14* 469 GC, Ibru s (0), e (0), m (1), gi (0), f (0), lu (1) - SD SD SD NR NR NR Stabilized lung function
15* 1864 CsA 10 s (1), e (1), m (2), gi (0), f (2), lu (3) L SD PR PR PR PR NR Increased mobility and improved lung symptoms
Median 1848 7
1/3/6/9/12-month RR 1/3/6/12-month response rate, respectively; GC glucocorticoid; E everolimus; MMF mycophenolate mofetil; Rux ruxolitinib; CsA cyclosporine A; Bari baricitinib; Ima imatinib; Tac tacrolimus; Toc tocilizumab; Ibru ibrutinib; s skin; e eyes; m mouth; f fascia; lu lungs; ge genital; S sclerotic features; L lichen planus-like features; PD progressive disease; SD stable disease; PR partial response; MR mixed response; NR not reached; Treg regulatory T cells; IS immunosuppression; PAD peripheral artery disease; QOL quality of life; AIHA autoimmune hemolytic anemia; *ongoing therapy
Response to abatacept at 1 month
One month after first administration of abatacept, the patient (7%) with AIHA showed CR, 5 (33%) patients had PR, one patient (7%) showed MR with improved lung function but progressive oral affection, and 8 patients (53%) presented with SD. None of the patients required start of an additional immunosuppressive therapy. The overall response rate (ORR) at 1 month was 40%, and failure-free survival (FFS) was 100%.
Response to abatacept at 3 months
At 3 months after start of abatacept therapy, one patient showed CR (7%), 5 (33%) patients had PR, one patient showed MR (7%), and 6 patients (40%) had SD. One patient who had SD started a new immunosuppression and another patient with a PR succumbed to infectious complications of severe peripheral artery disease unrelated to abatacept. ORR at 3 months was therefore 40% with an FFS of 87%.
Response to abatacept at 6 and 9 months
The 6 months follow-up was reached by nine patients with one patient remaining in CR (7%), four patients achieving PR (27%), one MR (7%) with sustained stabilized lung function but impaired oral affection, and two patients with SD (13%). At termination of our analysis, one patient was still treated with abatacept but has not reached the 6 months follow-up yet. One patient with PR started a new IS with ibrutinib and tocilizumab, and another patient who was in SD discontinued abatacept and was switched to tofacitinib due to persisting arthralgia. One highly comorbid patient with preexisting aortic valve insufficiency died due to aortic valve rupture. Thus, the ORR at 6 months was 33% with an FFS of 64%.
Nine months after initiation of abatacept treatment, four patients still received therapy and two patients currently still receiving abatacept have not reached the time point yet. Of the remaining patients, three showed a PR (20%), one patient discontinued abatacept due to sustained and not improved oral ulcers, and another patient died due to urosepsis, displaying an ORR of 23% with an FFS of 31%.
Response to abatacept at 12 months
At 12 months, three patients were still treated with abatacept, and three who currently receive abatacept therapy have not reached the time point yet. Three patients still had PR (25%) resulting in an ORR of 25% with FFS of 25%.
Response in patients with lung involvement of cGvHD
Interestingly, we observed that patients with lung involvement (n = 9) particularly benefitted from therapy with abatacept with an overall response rate of 89% based on improvement in lung severity score (n = 6), lung function as measured by FEV1 in Fig. 1 (n = 4) or both (n = 3). Of note, although only a stabilization on abatacept was achieved, they experienced prior constant loss of FEV1 as shown in Fig. 1. Of note, all patients received in parallel therapy with FAM (fluticasone, azithromycine, montelukast) partly in combination with beta-agonists which had already been applied > 1 month before abatacept initiation without response (Fig. 2).Fig. 2 Forced expiratory volume % before and during abatacept therapy
Infectious and other complications during abatacept
Adverse events (AE) and serious adverse events (SAE) during abatacept treatment are illustrated in Table 3. In general, abatacept administration was well tolerated; however, one patient repeatedly showed nausea, vomiting, diarrhea, fever, and fatigue for several days repeatedly upon infusion leading to termination of treatment after 7 applications. Another patient showed alopecia during treatment. Three of the patients included in the analysis developed significant infectious complications requiring hospital admission with one highly comorbid patient succumbing to urosepsis, and another patient already mentioned died due to infectious complications associated with severe peripheral artery disease unrelated to cGvHD.Table 3 Adverse and serious adverse events of abatacept treatment
Patient # AE SAE Specification
1 Yes No Fatigue, diarrhea, fever
2 No Yes Death due to gram-negative sepsis 70 days after last abatacept dose
3 No No -
4 No No -
5 No No -
6 No Yes Death due to urosepsis 24 days after last abatacept dose
7 No Yes Death due to infectious complications of peripheral artery disease
8 No No -
9 No No -
10 Yes No Alopecia after abatacept initiation
11 No No -
12 No Yes Hospital admission due to influenza A pneumonia
13 No No -
14 No No -
15 Yes No Bone pain after infusion
Discussion
cGvHD occurs with an incidence of 30–70% in patients undergoing allo-HSCT [21], and as it reduces quality of life and significantly contributes to NRM/TRM, there is still a high clinical need for effective second-line treatments [28, 29]. The underlying complex pathophysiology of cGvHD involves both B and T cell immunity and results in pleiotropic clinical manifestations resembling various autoimmune diseases [21]. Due to the involvement of auto- und alloreactive T cells in the development and course of cGvHD, there is high rationale for the use of costimulation blockade via the CTLA-4 pathway [20]. The introduction of the immunomodulatory drug abatacept has significantly improved the therapy for rheumatoid arthritis patients not responding sufficiently to conventional disease modifying antirheumatic drugs and has in this context shown efficacy and improvement of quality of life [19, 30, 31]. Based on observations in preclinical models, abatacept has been tested in combination with a CD25 monoclonal antibody in pediatric recipients of haploidentical allo-HSCT for the treatment of hyperacute GvHD, where it has shown efficacy [32]. Moreover, the safety and efficacy of abatacept for the prevention of aGvHD and treatment of SR-cGvHD were recently evaluated with promising results in phase 1 clinical trials [25, 33], and subsequent randomized phase 2 trials have been initiated (NCT0174313; NCT01954979).
In this retrospective analysis of cGvHD patients treated with abatacept at four centers, we observed a best overall response rate of 40%, which is comparable to the clinical response rate of 44% recently reported by Nahas et al. [25]. Despite the low number of patients and the retrospective character of the analysis, we observed that in particular patients with bronchiolitis obliterans syndrome (BOS) showed substantial clinical improvement after abatacept application with durable responses, stabilized lung function (Fig. 1), albeit this was not reflected by an improvement in lung grading in all patients. Given the frequently irreversible character of lung involvement due to fibrotic remodeling, we consider clinical improvement, lowering of oxygen demand, and stabilized lung function as relevant response parameters, especially in our patient cohort with mostly severe cGVHD [34]. Interestingly, it has been reported for several autoimmune diseases that costimulation blockade of the CTLA-4 axis selectively decreases the proportion of T follicular helper cells, thereby reducing T cell help for germinal center B cells [35–37]. Given that BOS is explicitly characterized by disturbance of B cell homeostasis with increased CD19+CD21- B cells and excess of B cell activation factor (BAFF) [38], abatacept might target Tfh cells in this context, which would at least partially explain the particular improvement of patients with BOS in our study. In addition, we observed a complete response in a steroid and rituximab refractory AIHA patient as previously described [39]. Despite not meeting NIH diagnostic criteria for cGvHD, we included this patient in our analysis since it has recently been reported that based on biomarker profiles, patients with signs of immune mediated damage not diagnostic for cGvHD do not significantly differ from those showing diagnostic signs of cGvHD suggesting that the current NIH diagnostic criteria may not involve all targets of cGvHD [40, 41]. Noteworthy, in the phase 1 clinical trial reported by Nahas et al., a reduction of corticosteroid usage of 51.3% was reported, while the authors state that this effect might have been overestimated due to the not blinded or randomized design of the study. In this regard, we did not observe consistent steroid reduction in patients responding to abatacept, yet most of our patients received a relatively low corticosteroid dose at start of abatacept. Interestingly, it has been reported in a preclinical model of chronic lung allograft dysfunction that bronchiolitis obliterans can be attenuated by CTLA-4-Ig administration presumably by promoting LAG3+Treg mediated anti-inflammatory effects providing a potential mechanistic explanation for the observed clinical response [42]. Of note, progression of cGvHD within three months was indicative for treatment failure, and all patients, who achieved at least a PR, were responding in the first three months. Thus, based on our experience, we would suggest discontinuing abatacept treatment, if patients do not show a response within this period. Overall, abatacept seems to be a relevant treatment option for patients with cGvHD, particularly for patients with BOS, but this has to be further investigated in future clinical trials.
Funding
Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projekt-ID 324392634 - TRR221, subproject B10 (D.W.), and by the ReForM program of the University of Regensburg (T.W.).
Declarations
Conflict of interest
D. W. received honoraria from Mallinckrodt, Novartis, Takeda, MACO, and Neovii.
The authors declare that they have no conflict of interest.
Informed consent
Informed consent was obtained from all patients for being included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Matthias Fante and Daniel Wolff contributed equally to this work. | ABATACEPT | DrugsGivenReaction | CC BY | 33515310 | 18,904,711 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Urosepsis'. | Abatacept as salvage therapy in chronic graft-versus-host disease-a retrospective analysis.
The immunomodulatory fusion protein abatacept has recently been investigated for the treatment of steroid-refractory chronic graft-versus-host disease (cGvHD) in a phase 1 clinical trial. We analyzed the safety and efficacy of abatacept for cGvHD therapy in a retrospective study with 15 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received abatacept for cGvHD with a median age of 49 years. Grading was performed as part of the clinical routine according to the National Institute of Health's (NIH) consensus criteria at initiation of abatacept and 1, 3, 6, 9 and 12 months thereafter. The median time of follow-up was 191 days (range 55-393 days). Best overall response rate (ORR) was 40%. In particular, patients with bronchiolitis obliterans syndrome showed significant clinical improvement and durable responses following abatacept treatment with a response rate of 89% based on improvement in lung severity score (n = 6) or stabilized lung function (n = 4) or both (n = 3). Infectious complications CTCAE °III or higher were observed in 3/15 patients. None of the patients relapsed from the underlying malignancy. Thus, abatacept appears to be a promising treatment option for cGvHD, in particular for patients with lung involvement. However, further evaluation within a phase 2 clinical trial is required.
Introduction
While allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established, potentially curative therapy for several malignant and benign hematologic diseases, chronic graft-versus-host disease (cGvHD) remains a major complication after allo-HSCT. cGvHD occurs in up to 70% of patients after allo-HSCT and significantly contributes to impaired quality of life and non-relapse mortality (NRM)/transplant-related mortality (TRM) [1–5].
Corticosteroids represent the backbone of cGVHD treatment, but contribute to an already high morbidity and mortality by causing complications such as osteoporosis, myopathy, avascular necrosis, and glaucoma [3, 6]. A substantial number of patients does not respond to corticosteroids alone and require second-line therapy with the recently FDA-approved Bruton’s tyrosine kinase inhibitor ibrutinib or extracorporeal photopheresis [5, 7–9]. Further treatment options are usually based on retrospective or phase 1/2 clinical studies and show limited efficacy in a significant proportion of patients despite harboring the risk of toxicity including infectious complications [10–14].
Abatacept is a novel, first in class immunomodulatory drug exerting its effect by costimulatory blockade and is applied for the treatment of rheumatoid arthritis and other rheumatological diseases [15–17]. It is a recombinant fusion protein comprised of the extracellular domain of the immune checkpoint protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4) fused to the Fc fragment of IgG1 [18]. By binding with high affinity to the costimulatory receptors CD80 and CD86 on antigen presenting cells (APCs), it counteracts the costimulatory signal mediated by the ligand CD28, which is required for full T cell activation [19].
The highly complex pathophysiology of cGvHD is still poorly understood. Apart from alloreactive donor T cell responses, it involves aberrant innate immune signaling, endothelial cell injury, dysfunctional central tolerance induction (due to thymic damage as a result of the conditioning regimen or alloreactive T cells), insufficient de novo development of regulatory T cells (Treg), dysregulation of B cells, and cytokine signaling eventually resulting in chronic inflammation and fibrotic remodeling [20–22].
Since cGvHD is at least in part mediated by host reactive T cells stimulated by allogeneic antigens [23], there is high rationale for abatacept as a treatment option in cGvHD, and it has been reported that CTLA-4 blockade can prevent aGvHD and cGvHD and even reverse cGvHD in murine models [24]. Recently, abatacept has received breakthrough approval by the American Food and Drug Administration (FDA) for the prevention of acute GvHD and has shown efficacy in a phase 1 clinical trial for patients with steroid-refractory cGvHD, albeit with relatively low patient numbers [25].
Therefore, we analyzed the efficacy and safety of abatacept for the treatment of advanced cGvHD in a multicentric retrospective study.
Patients and methods
Patients
In this retrospective analysis, patients treated with abatacept for cGvHD between 2018 and 2020 at the University Hospital Regensburg (Germany), University Hospital Giessen and Marburg (Germany), University Hospital and Karolinska Institutet (Stockholm, Sweden) and University Hospital La Paz (Madrid, Spain) were included into the analysis approved by the institutional ethics review board (no.19-1586-104). Documentation of cGvHD was performed as part of clinical routine using the diagnosis and response criteria according to the National Institute of Health (NIH) consensus guidelines [26]. No new immunosuppressive agent was applied within at least 4 weeks before abatacept therapy, and response assessment was discontinued upon requirement of any additional immunosuppressive treatment post abatacept therapy. Patients received abatacept intravenously at a dose of 10 mg/kg body weight (maximum 800 mg) every 2 weeks for the first three doses and then every 4 weeks.
Definition of abatacept response and adverse events
Response to abatacept was assessed at 1, 3, 6, 9, and 12 months after start of therapy. In case of treatment with an additional immunosuppressive agent, the last response assessment for abatacept was performed at onset of new therapy. Last follow-up of the present analysis was January 2020. Complete remission (CR) was defined as resolution of all organ manifestations of cGvHD. Improvement of at least one organ grade without progression of cGvHD at other organs was classified as partial response (PR); mixed response was defined as simultaneous improvement in one organ and progression in another organ. Patients who showed no change in organ grading were classified as stable disease (SD). Failure-free survival (FFS) was defined as absence of relapse or non-relapse mortality or addition of further systemic therapy. Overall response rates (ORR) were calculated based on intention to treat analysis. Infectious complications were assessed and classified according to the common terminology criteria for adverse events version 5.0 (CTCAE 5.0) with toxicities captured in the analysis starting from grade III.
Results
Patient characteristics
We treated 15 patients with abatacept for cGvHD at our centers between 2018 and 2020. Among those patients, the diagnoses leading to allo-HSCT were myeloid disorders (acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasia (MPN)) in 10 patients, lymphatic malignancies (acute lymphoblastic leukemia (ALL), and Hodgkin lymphoma (HL)) in four patients and one patient suffering from CTLA-4 haploinsufficiency.
All patients had received peripheral blood stem cells (PBSC) as graft source with 11 patients grafted from an HLA-matched sibling (5 patients) or an unrelated donor (8 patients). HLA-matched donors were defined as 10/10 match. One patient had received an HLA-C mismatched graft from an unrelated donor, and one patient received a haploidentical graft from a related donor. Acute GvHD grade II or higher according to Glucksberg criteria occurred in 11 patients (85%). cGvHD onset was quiescent in 8 patients, de novo in three patients and progressive in four patients. Most of the patients (n = 12; 80%), who received abatacept, had severe cGvHD. One patient included in the analysis had mild cGvHD (prior history of moderate cGvHD) and received abatacept due to intolerance to other immunosuppressive agents. One patient was treated for autoimmune-hemolytic anemia (AIHA) refractory to corticosteroids and rituximab not fulfilling the NIH criteria for cGvHD falling in the category “undefined other cGvHD” [26, 27]. The majority of the patients had steroid dependent cGvHD (n = 10, 67%, all others steroid-refractory cGvHD (n = 5; 33%)). A platelet count < 100/nl was observed in 4 patients (27%) at the time of abatacept initiation.
The most common organ manifestations of cGvHD were skin (n = 11; 73%), lung (n = 11; 73%), eyes (n = 10; 67%), and oral cavity (n = 10; 67%). Abatacept was initiated on median day 1848 (range 432–7953) after allo-HSCT and on day 1592 (range 28–7864) after cGvHD onset, respectively. The corticosteroid dose at abatacept initiation was 0.34 mg/kg in median (range 0,12–2 mg/kg). The patients included in the analysis had received a median of 4.6 prior treatment lines (range 2–5) for cGvHD. Within 3 months before abatacept treatment was started, most patients did not undergo new immunosuppressive treatments (80%). The remaining patients (20%), who underwent new immunosuppressive treatments within 3 months, were progressive or refractory to the initiated treatment.
Median follow-up after treatment was 179 days (range 55–393). Patient characteristics including age, gender, diagnosis, donor type, stem cell source, conditioning regimen, GvHD prophylaxis, history of acute GvHD, and chronic GvHD are shown in Table 1.Table 1 Patient characteristics
Patient characteristics Value
Patients 15
Female, n (%) 10
Male, n (%) 5
Age, median (range)* 49 (5–70)
Diagnosis
AML, n (%) 7 (47)
ALL, n (%) 2 (13)
MPN (%) 3 (15)
Others, n (%) 3 (15)
Donor type
HLA-matched unrelated, n (%) 7 (47)
HLA-mismatched unrelated, n (%) 1 (7)
HLA-matched related, n (%) 6 (40)
HLA-mismatched related, n (%) 0
Haploidentical related, n (%) 1 (7)
Sex mismatch: female to male
Yes, n (%) 1 (7)
No, n (%) 14 (93)
Stem cell source
Peripheral blood stem cells, n (%) 14 (93)
Bone marrow, n (%) 1 (7)
GvHD prophylaxis
ATG/CsA/MTX, n (%) 3 (20)
CsA/MTX, n (%) 5 (33)
CsA/MMF, n (%) 1 (7)
Other 6 (40)
History of aGvHD
Grades 0–I, n (%) 4 (27)
Grades II–IV, n (%) 11 (73)
Characteristics Value
Onset of cGvHD after allo-SCT, median days (range) 256 (76–597)
Time point of abatacept treatment after allo-SCT, median days, (range) 1848 (432–7953)
Time point of abatacept treatment after cGvHD onset, median days, (range) 1592 (133–7864)
Age at abatacept initiation, median (range) 49 (5–70)
Number of abatacept doses, median (range) 7.1 (1–20)
cGvHD, n (%)
Mild 1 (7)
Moderate 0
Severe
non-NIH defined (AIHA)
13 (87)
1 (7)
Steroid response of cGvHD
Steroid resistance 5 (33)
Steroid dependence 10 (67)
Number of organ involvement of cGvHD, n (%)
One 1 (7)
Two 1 (7)
Three 5 (33)
Four or more 8 (53)
Type of cGvHD organ involvement, n (%)
Skin 11 (73)
Oral 10 (67)
Eyes 10 (67)
Liver 2 (13)
Gut 4 (27)
Lung 11 (73)
Musculoskeletal 7 (47)
Genital 2 (13)
AIHA 1 (7)
ISM at the beginning of abatacept, n (%)
No ISM 0
One ISM 5 (33)
Two ISM 8 (53)
Three or more ISM 2 (13)
Number of prior therapies before abatacept, n (%)
One 2 (13)
Two 2 13)
Three 1 (7)
Four or more prior therapies 10 (67)
New ISM within 3 months before abatacept, n (%)
Yes 3 (20)
No 12 (80)
n number of patients, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, MPN myeloproliferative neoplasia, HLA human leukocyte antigen, ATG anti-thymocyte globulin, CsA ciclosporin A, MTX methotrexate, MMF mycophenolate mofetil, GvHD graft-versus-host disease, aGvHD acute GvHD, cGvHD chronic GvHD, ISM immunosuppressive medication
Response to abatacept
Response to abatacept treatment is illustrated in Fig. 1 and Table 2 at the different time points of this analysis.Fig. 1 Clinical course during abatacept treatment
Table 2 Duration of abatacept treatment and clinical course
Patient # Day of start IS at start # of doses Organ involvement (grade) at start Skin features at start 1 m RR 2 m RR 3 m RR 6 m RR 9 m RR 12 m RR Follow up
1 7953 GC, E, MMF 7 s (0), e (3), m (0), f (0), lu (3) - SD SD SD SD - - Stabilized lung function, abatacept discontinued due to prolonged fatigue and diarrhea after administration
2 1596 GC, Rux 6 s (3), e (1), m (1), f (2), lu (2) S PR PR PR - - - Improvement of lung GvHD, new IS with ibrutinib and tocilizumab after 6 months
3 3261 GC, CsA 2 s (3), e (0), m (2), f (2), lu (0) S SD SD SD SD - - New IS with daratumumab after no improvement of oral ulcers
4 1425 GC 4 s (3), e (1), m (1), f (2), lu (2) S SD MR SD - - - Death due to aortic valve rupture (preexisting aortic valve insufficiency)
5 949 GC, Rux 3 s (3), e (2), m (0), f (2), lu (0) S SD SD - - - - New IS with Treg after 2 months
6 722 GC 10 s (0), e (3), m (0), f (0), lu (3) - PR PR PR PR - - Stabilized lung GvHD and improved functional capacity, death due to sepsis 9 months after abatacept start
7 1318 GC 1 s (0), e (0), m (1), f (0), lu (0) - PR PR - - - - Abatacept was given due to intolerance to IS agents and multiple infectious complications; death due to infectious complications of PAD
8 4587 GC, Bari 5 s (3), e (0), m (0), f (2), lu (0) S SD SD SD - - - New IS with tofacitinib after persisting arthralgia
9* 1311 GC, Ima 14 s (1), e (1), m (1), gi (1), f (0), lu (3) L PR PR PR PR PR PR Durable improvement of lung and skin GvHD. Less oxygen demand, reduced coughing
10* 432 GC, E 14 s (3), e (1), m (1), f (0), lu (0) S SD SD PR PR PR PR Improvement of ocular GvHD
11 1162 GC, Tac 9 s (1), e (3), m (1), f (0), lu (3) L MR MR MR MR - - Stabilized lung function, progressive oral affection, new IS with ruxolitinib after 9 months
12* 517 Toc 13 s (2), m (1), gi (1), li (1), f (0), lu (3) L PR PR PR PR PR PR Complete resolution of s, m, gi and li GvHD. Significant improvement of lung GvHD (reduction from grades 3 to 1)
13* 157 GC 4 AIHA - CR CR CR CR NR NR Complete resolution of AIHA
14* 469 GC, Ibru s (0), e (0), m (1), gi (0), f (0), lu (1) - SD SD SD NR NR NR Stabilized lung function
15* 1864 CsA 10 s (1), e (1), m (2), gi (0), f (2), lu (3) L SD PR PR PR PR NR Increased mobility and improved lung symptoms
Median 1848 7
1/3/6/9/12-month RR 1/3/6/12-month response rate, respectively; GC glucocorticoid; E everolimus; MMF mycophenolate mofetil; Rux ruxolitinib; CsA cyclosporine A; Bari baricitinib; Ima imatinib; Tac tacrolimus; Toc tocilizumab; Ibru ibrutinib; s skin; e eyes; m mouth; f fascia; lu lungs; ge genital; S sclerotic features; L lichen planus-like features; PD progressive disease; SD stable disease; PR partial response; MR mixed response; NR not reached; Treg regulatory T cells; IS immunosuppression; PAD peripheral artery disease; QOL quality of life; AIHA autoimmune hemolytic anemia; *ongoing therapy
Response to abatacept at 1 month
One month after first administration of abatacept, the patient (7%) with AIHA showed CR, 5 (33%) patients had PR, one patient (7%) showed MR with improved lung function but progressive oral affection, and 8 patients (53%) presented with SD. None of the patients required start of an additional immunosuppressive therapy. The overall response rate (ORR) at 1 month was 40%, and failure-free survival (FFS) was 100%.
Response to abatacept at 3 months
At 3 months after start of abatacept therapy, one patient showed CR (7%), 5 (33%) patients had PR, one patient showed MR (7%), and 6 patients (40%) had SD. One patient who had SD started a new immunosuppression and another patient with a PR succumbed to infectious complications of severe peripheral artery disease unrelated to abatacept. ORR at 3 months was therefore 40% with an FFS of 87%.
Response to abatacept at 6 and 9 months
The 6 months follow-up was reached by nine patients with one patient remaining in CR (7%), four patients achieving PR (27%), one MR (7%) with sustained stabilized lung function but impaired oral affection, and two patients with SD (13%). At termination of our analysis, one patient was still treated with abatacept but has not reached the 6 months follow-up yet. One patient with PR started a new IS with ibrutinib and tocilizumab, and another patient who was in SD discontinued abatacept and was switched to tofacitinib due to persisting arthralgia. One highly comorbid patient with preexisting aortic valve insufficiency died due to aortic valve rupture. Thus, the ORR at 6 months was 33% with an FFS of 64%.
Nine months after initiation of abatacept treatment, four patients still received therapy and two patients currently still receiving abatacept have not reached the time point yet. Of the remaining patients, three showed a PR (20%), one patient discontinued abatacept due to sustained and not improved oral ulcers, and another patient died due to urosepsis, displaying an ORR of 23% with an FFS of 31%.
Response to abatacept at 12 months
At 12 months, three patients were still treated with abatacept, and three who currently receive abatacept therapy have not reached the time point yet. Three patients still had PR (25%) resulting in an ORR of 25% with FFS of 25%.
Response in patients with lung involvement of cGvHD
Interestingly, we observed that patients with lung involvement (n = 9) particularly benefitted from therapy with abatacept with an overall response rate of 89% based on improvement in lung severity score (n = 6), lung function as measured by FEV1 in Fig. 1 (n = 4) or both (n = 3). Of note, although only a stabilization on abatacept was achieved, they experienced prior constant loss of FEV1 as shown in Fig. 1. Of note, all patients received in parallel therapy with FAM (fluticasone, azithromycine, montelukast) partly in combination with beta-agonists which had already been applied > 1 month before abatacept initiation without response (Fig. 2).Fig. 2 Forced expiratory volume % before and during abatacept therapy
Infectious and other complications during abatacept
Adverse events (AE) and serious adverse events (SAE) during abatacept treatment are illustrated in Table 3. In general, abatacept administration was well tolerated; however, one patient repeatedly showed nausea, vomiting, diarrhea, fever, and fatigue for several days repeatedly upon infusion leading to termination of treatment after 7 applications. Another patient showed alopecia during treatment. Three of the patients included in the analysis developed significant infectious complications requiring hospital admission with one highly comorbid patient succumbing to urosepsis, and another patient already mentioned died due to infectious complications associated with severe peripheral artery disease unrelated to cGvHD.Table 3 Adverse and serious adverse events of abatacept treatment
Patient # AE SAE Specification
1 Yes No Fatigue, diarrhea, fever
2 No Yes Death due to gram-negative sepsis 70 days after last abatacept dose
3 No No -
4 No No -
5 No No -
6 No Yes Death due to urosepsis 24 days after last abatacept dose
7 No Yes Death due to infectious complications of peripheral artery disease
8 No No -
9 No No -
10 Yes No Alopecia after abatacept initiation
11 No No -
12 No Yes Hospital admission due to influenza A pneumonia
13 No No -
14 No No -
15 Yes No Bone pain after infusion
Discussion
cGvHD occurs with an incidence of 30–70% in patients undergoing allo-HSCT [21], and as it reduces quality of life and significantly contributes to NRM/TRM, there is still a high clinical need for effective second-line treatments [28, 29]. The underlying complex pathophysiology of cGvHD involves both B and T cell immunity and results in pleiotropic clinical manifestations resembling various autoimmune diseases [21]. Due to the involvement of auto- und alloreactive T cells in the development and course of cGvHD, there is high rationale for the use of costimulation blockade via the CTLA-4 pathway [20]. The introduction of the immunomodulatory drug abatacept has significantly improved the therapy for rheumatoid arthritis patients not responding sufficiently to conventional disease modifying antirheumatic drugs and has in this context shown efficacy and improvement of quality of life [19, 30, 31]. Based on observations in preclinical models, abatacept has been tested in combination with a CD25 monoclonal antibody in pediatric recipients of haploidentical allo-HSCT for the treatment of hyperacute GvHD, where it has shown efficacy [32]. Moreover, the safety and efficacy of abatacept for the prevention of aGvHD and treatment of SR-cGvHD were recently evaluated with promising results in phase 1 clinical trials [25, 33], and subsequent randomized phase 2 trials have been initiated (NCT0174313; NCT01954979).
In this retrospective analysis of cGvHD patients treated with abatacept at four centers, we observed a best overall response rate of 40%, which is comparable to the clinical response rate of 44% recently reported by Nahas et al. [25]. Despite the low number of patients and the retrospective character of the analysis, we observed that in particular patients with bronchiolitis obliterans syndrome (BOS) showed substantial clinical improvement after abatacept application with durable responses, stabilized lung function (Fig. 1), albeit this was not reflected by an improvement in lung grading in all patients. Given the frequently irreversible character of lung involvement due to fibrotic remodeling, we consider clinical improvement, lowering of oxygen demand, and stabilized lung function as relevant response parameters, especially in our patient cohort with mostly severe cGVHD [34]. Interestingly, it has been reported for several autoimmune diseases that costimulation blockade of the CTLA-4 axis selectively decreases the proportion of T follicular helper cells, thereby reducing T cell help for germinal center B cells [35–37]. Given that BOS is explicitly characterized by disturbance of B cell homeostasis with increased CD19+CD21- B cells and excess of B cell activation factor (BAFF) [38], abatacept might target Tfh cells in this context, which would at least partially explain the particular improvement of patients with BOS in our study. In addition, we observed a complete response in a steroid and rituximab refractory AIHA patient as previously described [39]. Despite not meeting NIH diagnostic criteria for cGvHD, we included this patient in our analysis since it has recently been reported that based on biomarker profiles, patients with signs of immune mediated damage not diagnostic for cGvHD do not significantly differ from those showing diagnostic signs of cGvHD suggesting that the current NIH diagnostic criteria may not involve all targets of cGvHD [40, 41]. Noteworthy, in the phase 1 clinical trial reported by Nahas et al., a reduction of corticosteroid usage of 51.3% was reported, while the authors state that this effect might have been overestimated due to the not blinded or randomized design of the study. In this regard, we did not observe consistent steroid reduction in patients responding to abatacept, yet most of our patients received a relatively low corticosteroid dose at start of abatacept. Interestingly, it has been reported in a preclinical model of chronic lung allograft dysfunction that bronchiolitis obliterans can be attenuated by CTLA-4-Ig administration presumably by promoting LAG3+Treg mediated anti-inflammatory effects providing a potential mechanistic explanation for the observed clinical response [42]. Of note, progression of cGvHD within three months was indicative for treatment failure, and all patients, who achieved at least a PR, were responding in the first three months. Thus, based on our experience, we would suggest discontinuing abatacept treatment, if patients do not show a response within this period. Overall, abatacept seems to be a relevant treatment option for patients with cGvHD, particularly for patients with BOS, but this has to be further investigated in future clinical trials.
Funding
Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projekt-ID 324392634 - TRR221, subproject B10 (D.W.), and by the ReForM program of the University of Regensburg (T.W.).
Declarations
Conflict of interest
D. W. received honoraria from Mallinckrodt, Novartis, Takeda, MACO, and Neovii.
The authors declare that they have no conflict of interest.
Informed consent
Informed consent was obtained from all patients for being included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Matthias Fante and Daniel Wolff contributed equally to this work. | ABATACEPT | DrugsGivenReaction | CC BY | 33515310 | 18,904,612 | 2021-03 |
What was the administration route of drug 'ABATACEPT'? | Abatacept as salvage therapy in chronic graft-versus-host disease-a retrospective analysis.
The immunomodulatory fusion protein abatacept has recently been investigated for the treatment of steroid-refractory chronic graft-versus-host disease (cGvHD) in a phase 1 clinical trial. We analyzed the safety and efficacy of abatacept for cGvHD therapy in a retrospective study with 15 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received abatacept for cGvHD with a median age of 49 years. Grading was performed as part of the clinical routine according to the National Institute of Health's (NIH) consensus criteria at initiation of abatacept and 1, 3, 6, 9 and 12 months thereafter. The median time of follow-up was 191 days (range 55-393 days). Best overall response rate (ORR) was 40%. In particular, patients with bronchiolitis obliterans syndrome showed significant clinical improvement and durable responses following abatacept treatment with a response rate of 89% based on improvement in lung severity score (n = 6) or stabilized lung function (n = 4) or both (n = 3). Infectious complications CTCAE °III or higher were observed in 3/15 patients. None of the patients relapsed from the underlying malignancy. Thus, abatacept appears to be a promising treatment option for cGvHD, in particular for patients with lung involvement. However, further evaluation within a phase 2 clinical trial is required.
Introduction
While allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established, potentially curative therapy for several malignant and benign hematologic diseases, chronic graft-versus-host disease (cGvHD) remains a major complication after allo-HSCT. cGvHD occurs in up to 70% of patients after allo-HSCT and significantly contributes to impaired quality of life and non-relapse mortality (NRM)/transplant-related mortality (TRM) [1–5].
Corticosteroids represent the backbone of cGVHD treatment, but contribute to an already high morbidity and mortality by causing complications such as osteoporosis, myopathy, avascular necrosis, and glaucoma [3, 6]. A substantial number of patients does not respond to corticosteroids alone and require second-line therapy with the recently FDA-approved Bruton’s tyrosine kinase inhibitor ibrutinib or extracorporeal photopheresis [5, 7–9]. Further treatment options are usually based on retrospective or phase 1/2 clinical studies and show limited efficacy in a significant proportion of patients despite harboring the risk of toxicity including infectious complications [10–14].
Abatacept is a novel, first in class immunomodulatory drug exerting its effect by costimulatory blockade and is applied for the treatment of rheumatoid arthritis and other rheumatological diseases [15–17]. It is a recombinant fusion protein comprised of the extracellular domain of the immune checkpoint protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4) fused to the Fc fragment of IgG1 [18]. By binding with high affinity to the costimulatory receptors CD80 and CD86 on antigen presenting cells (APCs), it counteracts the costimulatory signal mediated by the ligand CD28, which is required for full T cell activation [19].
The highly complex pathophysiology of cGvHD is still poorly understood. Apart from alloreactive donor T cell responses, it involves aberrant innate immune signaling, endothelial cell injury, dysfunctional central tolerance induction (due to thymic damage as a result of the conditioning regimen or alloreactive T cells), insufficient de novo development of regulatory T cells (Treg), dysregulation of B cells, and cytokine signaling eventually resulting in chronic inflammation and fibrotic remodeling [20–22].
Since cGvHD is at least in part mediated by host reactive T cells stimulated by allogeneic antigens [23], there is high rationale for abatacept as a treatment option in cGvHD, and it has been reported that CTLA-4 blockade can prevent aGvHD and cGvHD and even reverse cGvHD in murine models [24]. Recently, abatacept has received breakthrough approval by the American Food and Drug Administration (FDA) for the prevention of acute GvHD and has shown efficacy in a phase 1 clinical trial for patients with steroid-refractory cGvHD, albeit with relatively low patient numbers [25].
Therefore, we analyzed the efficacy and safety of abatacept for the treatment of advanced cGvHD in a multicentric retrospective study.
Patients and methods
Patients
In this retrospective analysis, patients treated with abatacept for cGvHD between 2018 and 2020 at the University Hospital Regensburg (Germany), University Hospital Giessen and Marburg (Germany), University Hospital and Karolinska Institutet (Stockholm, Sweden) and University Hospital La Paz (Madrid, Spain) were included into the analysis approved by the institutional ethics review board (no.19-1586-104). Documentation of cGvHD was performed as part of clinical routine using the diagnosis and response criteria according to the National Institute of Health (NIH) consensus guidelines [26]. No new immunosuppressive agent was applied within at least 4 weeks before abatacept therapy, and response assessment was discontinued upon requirement of any additional immunosuppressive treatment post abatacept therapy. Patients received abatacept intravenously at a dose of 10 mg/kg body weight (maximum 800 mg) every 2 weeks for the first three doses and then every 4 weeks.
Definition of abatacept response and adverse events
Response to abatacept was assessed at 1, 3, 6, 9, and 12 months after start of therapy. In case of treatment with an additional immunosuppressive agent, the last response assessment for abatacept was performed at onset of new therapy. Last follow-up of the present analysis was January 2020. Complete remission (CR) was defined as resolution of all organ manifestations of cGvHD. Improvement of at least one organ grade without progression of cGvHD at other organs was classified as partial response (PR); mixed response was defined as simultaneous improvement in one organ and progression in another organ. Patients who showed no change in organ grading were classified as stable disease (SD). Failure-free survival (FFS) was defined as absence of relapse or non-relapse mortality or addition of further systemic therapy. Overall response rates (ORR) were calculated based on intention to treat analysis. Infectious complications were assessed and classified according to the common terminology criteria for adverse events version 5.0 (CTCAE 5.0) with toxicities captured in the analysis starting from grade III.
Results
Patient characteristics
We treated 15 patients with abatacept for cGvHD at our centers between 2018 and 2020. Among those patients, the diagnoses leading to allo-HSCT were myeloid disorders (acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasia (MPN)) in 10 patients, lymphatic malignancies (acute lymphoblastic leukemia (ALL), and Hodgkin lymphoma (HL)) in four patients and one patient suffering from CTLA-4 haploinsufficiency.
All patients had received peripheral blood stem cells (PBSC) as graft source with 11 patients grafted from an HLA-matched sibling (5 patients) or an unrelated donor (8 patients). HLA-matched donors were defined as 10/10 match. One patient had received an HLA-C mismatched graft from an unrelated donor, and one patient received a haploidentical graft from a related donor. Acute GvHD grade II or higher according to Glucksberg criteria occurred in 11 patients (85%). cGvHD onset was quiescent in 8 patients, de novo in three patients and progressive in four patients. Most of the patients (n = 12; 80%), who received abatacept, had severe cGvHD. One patient included in the analysis had mild cGvHD (prior history of moderate cGvHD) and received abatacept due to intolerance to other immunosuppressive agents. One patient was treated for autoimmune-hemolytic anemia (AIHA) refractory to corticosteroids and rituximab not fulfilling the NIH criteria for cGvHD falling in the category “undefined other cGvHD” [26, 27]. The majority of the patients had steroid dependent cGvHD (n = 10, 67%, all others steroid-refractory cGvHD (n = 5; 33%)). A platelet count < 100/nl was observed in 4 patients (27%) at the time of abatacept initiation.
The most common organ manifestations of cGvHD were skin (n = 11; 73%), lung (n = 11; 73%), eyes (n = 10; 67%), and oral cavity (n = 10; 67%). Abatacept was initiated on median day 1848 (range 432–7953) after allo-HSCT and on day 1592 (range 28–7864) after cGvHD onset, respectively. The corticosteroid dose at abatacept initiation was 0.34 mg/kg in median (range 0,12–2 mg/kg). The patients included in the analysis had received a median of 4.6 prior treatment lines (range 2–5) for cGvHD. Within 3 months before abatacept treatment was started, most patients did not undergo new immunosuppressive treatments (80%). The remaining patients (20%), who underwent new immunosuppressive treatments within 3 months, were progressive or refractory to the initiated treatment.
Median follow-up after treatment was 179 days (range 55–393). Patient characteristics including age, gender, diagnosis, donor type, stem cell source, conditioning regimen, GvHD prophylaxis, history of acute GvHD, and chronic GvHD are shown in Table 1.Table 1 Patient characteristics
Patient characteristics Value
Patients 15
Female, n (%) 10
Male, n (%) 5
Age, median (range)* 49 (5–70)
Diagnosis
AML, n (%) 7 (47)
ALL, n (%) 2 (13)
MPN (%) 3 (15)
Others, n (%) 3 (15)
Donor type
HLA-matched unrelated, n (%) 7 (47)
HLA-mismatched unrelated, n (%) 1 (7)
HLA-matched related, n (%) 6 (40)
HLA-mismatched related, n (%) 0
Haploidentical related, n (%) 1 (7)
Sex mismatch: female to male
Yes, n (%) 1 (7)
No, n (%) 14 (93)
Stem cell source
Peripheral blood stem cells, n (%) 14 (93)
Bone marrow, n (%) 1 (7)
GvHD prophylaxis
ATG/CsA/MTX, n (%) 3 (20)
CsA/MTX, n (%) 5 (33)
CsA/MMF, n (%) 1 (7)
Other 6 (40)
History of aGvHD
Grades 0–I, n (%) 4 (27)
Grades II–IV, n (%) 11 (73)
Characteristics Value
Onset of cGvHD after allo-SCT, median days (range) 256 (76–597)
Time point of abatacept treatment after allo-SCT, median days, (range) 1848 (432–7953)
Time point of abatacept treatment after cGvHD onset, median days, (range) 1592 (133–7864)
Age at abatacept initiation, median (range) 49 (5–70)
Number of abatacept doses, median (range) 7.1 (1–20)
cGvHD, n (%)
Mild 1 (7)
Moderate 0
Severe
non-NIH defined (AIHA)
13 (87)
1 (7)
Steroid response of cGvHD
Steroid resistance 5 (33)
Steroid dependence 10 (67)
Number of organ involvement of cGvHD, n (%)
One 1 (7)
Two 1 (7)
Three 5 (33)
Four or more 8 (53)
Type of cGvHD organ involvement, n (%)
Skin 11 (73)
Oral 10 (67)
Eyes 10 (67)
Liver 2 (13)
Gut 4 (27)
Lung 11 (73)
Musculoskeletal 7 (47)
Genital 2 (13)
AIHA 1 (7)
ISM at the beginning of abatacept, n (%)
No ISM 0
One ISM 5 (33)
Two ISM 8 (53)
Three or more ISM 2 (13)
Number of prior therapies before abatacept, n (%)
One 2 (13)
Two 2 13)
Three 1 (7)
Four or more prior therapies 10 (67)
New ISM within 3 months before abatacept, n (%)
Yes 3 (20)
No 12 (80)
n number of patients, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, MPN myeloproliferative neoplasia, HLA human leukocyte antigen, ATG anti-thymocyte globulin, CsA ciclosporin A, MTX methotrexate, MMF mycophenolate mofetil, GvHD graft-versus-host disease, aGvHD acute GvHD, cGvHD chronic GvHD, ISM immunosuppressive medication
Response to abatacept
Response to abatacept treatment is illustrated in Fig. 1 and Table 2 at the different time points of this analysis.Fig. 1 Clinical course during abatacept treatment
Table 2 Duration of abatacept treatment and clinical course
Patient # Day of start IS at start # of doses Organ involvement (grade) at start Skin features at start 1 m RR 2 m RR 3 m RR 6 m RR 9 m RR 12 m RR Follow up
1 7953 GC, E, MMF 7 s (0), e (3), m (0), f (0), lu (3) - SD SD SD SD - - Stabilized lung function, abatacept discontinued due to prolonged fatigue and diarrhea after administration
2 1596 GC, Rux 6 s (3), e (1), m (1), f (2), lu (2) S PR PR PR - - - Improvement of lung GvHD, new IS with ibrutinib and tocilizumab after 6 months
3 3261 GC, CsA 2 s (3), e (0), m (2), f (2), lu (0) S SD SD SD SD - - New IS with daratumumab after no improvement of oral ulcers
4 1425 GC 4 s (3), e (1), m (1), f (2), lu (2) S SD MR SD - - - Death due to aortic valve rupture (preexisting aortic valve insufficiency)
5 949 GC, Rux 3 s (3), e (2), m (0), f (2), lu (0) S SD SD - - - - New IS with Treg after 2 months
6 722 GC 10 s (0), e (3), m (0), f (0), lu (3) - PR PR PR PR - - Stabilized lung GvHD and improved functional capacity, death due to sepsis 9 months after abatacept start
7 1318 GC 1 s (0), e (0), m (1), f (0), lu (0) - PR PR - - - - Abatacept was given due to intolerance to IS agents and multiple infectious complications; death due to infectious complications of PAD
8 4587 GC, Bari 5 s (3), e (0), m (0), f (2), lu (0) S SD SD SD - - - New IS with tofacitinib after persisting arthralgia
9* 1311 GC, Ima 14 s (1), e (1), m (1), gi (1), f (0), lu (3) L PR PR PR PR PR PR Durable improvement of lung and skin GvHD. Less oxygen demand, reduced coughing
10* 432 GC, E 14 s (3), e (1), m (1), f (0), lu (0) S SD SD PR PR PR PR Improvement of ocular GvHD
11 1162 GC, Tac 9 s (1), e (3), m (1), f (0), lu (3) L MR MR MR MR - - Stabilized lung function, progressive oral affection, new IS with ruxolitinib after 9 months
12* 517 Toc 13 s (2), m (1), gi (1), li (1), f (0), lu (3) L PR PR PR PR PR PR Complete resolution of s, m, gi and li GvHD. Significant improvement of lung GvHD (reduction from grades 3 to 1)
13* 157 GC 4 AIHA - CR CR CR CR NR NR Complete resolution of AIHA
14* 469 GC, Ibru s (0), e (0), m (1), gi (0), f (0), lu (1) - SD SD SD NR NR NR Stabilized lung function
15* 1864 CsA 10 s (1), e (1), m (2), gi (0), f (2), lu (3) L SD PR PR PR PR NR Increased mobility and improved lung symptoms
Median 1848 7
1/3/6/9/12-month RR 1/3/6/12-month response rate, respectively; GC glucocorticoid; E everolimus; MMF mycophenolate mofetil; Rux ruxolitinib; CsA cyclosporine A; Bari baricitinib; Ima imatinib; Tac tacrolimus; Toc tocilizumab; Ibru ibrutinib; s skin; e eyes; m mouth; f fascia; lu lungs; ge genital; S sclerotic features; L lichen planus-like features; PD progressive disease; SD stable disease; PR partial response; MR mixed response; NR not reached; Treg regulatory T cells; IS immunosuppression; PAD peripheral artery disease; QOL quality of life; AIHA autoimmune hemolytic anemia; *ongoing therapy
Response to abatacept at 1 month
One month after first administration of abatacept, the patient (7%) with AIHA showed CR, 5 (33%) patients had PR, one patient (7%) showed MR with improved lung function but progressive oral affection, and 8 patients (53%) presented with SD. None of the patients required start of an additional immunosuppressive therapy. The overall response rate (ORR) at 1 month was 40%, and failure-free survival (FFS) was 100%.
Response to abatacept at 3 months
At 3 months after start of abatacept therapy, one patient showed CR (7%), 5 (33%) patients had PR, one patient showed MR (7%), and 6 patients (40%) had SD. One patient who had SD started a new immunosuppression and another patient with a PR succumbed to infectious complications of severe peripheral artery disease unrelated to abatacept. ORR at 3 months was therefore 40% with an FFS of 87%.
Response to abatacept at 6 and 9 months
The 6 months follow-up was reached by nine patients with one patient remaining in CR (7%), four patients achieving PR (27%), one MR (7%) with sustained stabilized lung function but impaired oral affection, and two patients with SD (13%). At termination of our analysis, one patient was still treated with abatacept but has not reached the 6 months follow-up yet. One patient with PR started a new IS with ibrutinib and tocilizumab, and another patient who was in SD discontinued abatacept and was switched to tofacitinib due to persisting arthralgia. One highly comorbid patient with preexisting aortic valve insufficiency died due to aortic valve rupture. Thus, the ORR at 6 months was 33% with an FFS of 64%.
Nine months after initiation of abatacept treatment, four patients still received therapy and two patients currently still receiving abatacept have not reached the time point yet. Of the remaining patients, three showed a PR (20%), one patient discontinued abatacept due to sustained and not improved oral ulcers, and another patient died due to urosepsis, displaying an ORR of 23% with an FFS of 31%.
Response to abatacept at 12 months
At 12 months, three patients were still treated with abatacept, and three who currently receive abatacept therapy have not reached the time point yet. Three patients still had PR (25%) resulting in an ORR of 25% with FFS of 25%.
Response in patients with lung involvement of cGvHD
Interestingly, we observed that patients with lung involvement (n = 9) particularly benefitted from therapy with abatacept with an overall response rate of 89% based on improvement in lung severity score (n = 6), lung function as measured by FEV1 in Fig. 1 (n = 4) or both (n = 3). Of note, although only a stabilization on abatacept was achieved, they experienced prior constant loss of FEV1 as shown in Fig. 1. Of note, all patients received in parallel therapy with FAM (fluticasone, azithromycine, montelukast) partly in combination with beta-agonists which had already been applied > 1 month before abatacept initiation without response (Fig. 2).Fig. 2 Forced expiratory volume % before and during abatacept therapy
Infectious and other complications during abatacept
Adverse events (AE) and serious adverse events (SAE) during abatacept treatment are illustrated in Table 3. In general, abatacept administration was well tolerated; however, one patient repeatedly showed nausea, vomiting, diarrhea, fever, and fatigue for several days repeatedly upon infusion leading to termination of treatment after 7 applications. Another patient showed alopecia during treatment. Three of the patients included in the analysis developed significant infectious complications requiring hospital admission with one highly comorbid patient succumbing to urosepsis, and another patient already mentioned died due to infectious complications associated with severe peripheral artery disease unrelated to cGvHD.Table 3 Adverse and serious adverse events of abatacept treatment
Patient # AE SAE Specification
1 Yes No Fatigue, diarrhea, fever
2 No Yes Death due to gram-negative sepsis 70 days after last abatacept dose
3 No No -
4 No No -
5 No No -
6 No Yes Death due to urosepsis 24 days after last abatacept dose
7 No Yes Death due to infectious complications of peripheral artery disease
8 No No -
9 No No -
10 Yes No Alopecia after abatacept initiation
11 No No -
12 No Yes Hospital admission due to influenza A pneumonia
13 No No -
14 No No -
15 Yes No Bone pain after infusion
Discussion
cGvHD occurs with an incidence of 30–70% in patients undergoing allo-HSCT [21], and as it reduces quality of life and significantly contributes to NRM/TRM, there is still a high clinical need for effective second-line treatments [28, 29]. The underlying complex pathophysiology of cGvHD involves both B and T cell immunity and results in pleiotropic clinical manifestations resembling various autoimmune diseases [21]. Due to the involvement of auto- und alloreactive T cells in the development and course of cGvHD, there is high rationale for the use of costimulation blockade via the CTLA-4 pathway [20]. The introduction of the immunomodulatory drug abatacept has significantly improved the therapy for rheumatoid arthritis patients not responding sufficiently to conventional disease modifying antirheumatic drugs and has in this context shown efficacy and improvement of quality of life [19, 30, 31]. Based on observations in preclinical models, abatacept has been tested in combination with a CD25 monoclonal antibody in pediatric recipients of haploidentical allo-HSCT for the treatment of hyperacute GvHD, where it has shown efficacy [32]. Moreover, the safety and efficacy of abatacept for the prevention of aGvHD and treatment of SR-cGvHD were recently evaluated with promising results in phase 1 clinical trials [25, 33], and subsequent randomized phase 2 trials have been initiated (NCT0174313; NCT01954979).
In this retrospective analysis of cGvHD patients treated with abatacept at four centers, we observed a best overall response rate of 40%, which is comparable to the clinical response rate of 44% recently reported by Nahas et al. [25]. Despite the low number of patients and the retrospective character of the analysis, we observed that in particular patients with bronchiolitis obliterans syndrome (BOS) showed substantial clinical improvement after abatacept application with durable responses, stabilized lung function (Fig. 1), albeit this was not reflected by an improvement in lung grading in all patients. Given the frequently irreversible character of lung involvement due to fibrotic remodeling, we consider clinical improvement, lowering of oxygen demand, and stabilized lung function as relevant response parameters, especially in our patient cohort with mostly severe cGVHD [34]. Interestingly, it has been reported for several autoimmune diseases that costimulation blockade of the CTLA-4 axis selectively decreases the proportion of T follicular helper cells, thereby reducing T cell help for germinal center B cells [35–37]. Given that BOS is explicitly characterized by disturbance of B cell homeostasis with increased CD19+CD21- B cells and excess of B cell activation factor (BAFF) [38], abatacept might target Tfh cells in this context, which would at least partially explain the particular improvement of patients with BOS in our study. In addition, we observed a complete response in a steroid and rituximab refractory AIHA patient as previously described [39]. Despite not meeting NIH diagnostic criteria for cGvHD, we included this patient in our analysis since it has recently been reported that based on biomarker profiles, patients with signs of immune mediated damage not diagnostic for cGvHD do not significantly differ from those showing diagnostic signs of cGvHD suggesting that the current NIH diagnostic criteria may not involve all targets of cGvHD [40, 41]. Noteworthy, in the phase 1 clinical trial reported by Nahas et al., a reduction of corticosteroid usage of 51.3% was reported, while the authors state that this effect might have been overestimated due to the not blinded or randomized design of the study. In this regard, we did not observe consistent steroid reduction in patients responding to abatacept, yet most of our patients received a relatively low corticosteroid dose at start of abatacept. Interestingly, it has been reported in a preclinical model of chronic lung allograft dysfunction that bronchiolitis obliterans can be attenuated by CTLA-4-Ig administration presumably by promoting LAG3+Treg mediated anti-inflammatory effects providing a potential mechanistic explanation for the observed clinical response [42]. Of note, progression of cGvHD within three months was indicative for treatment failure, and all patients, who achieved at least a PR, were responding in the first three months. Thus, based on our experience, we would suggest discontinuing abatacept treatment, if patients do not show a response within this period. Overall, abatacept seems to be a relevant treatment option for patients with cGvHD, particularly for patients with BOS, but this has to be further investigated in future clinical trials.
Funding
Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projekt-ID 324392634 - TRR221, subproject B10 (D.W.), and by the ReForM program of the University of Regensburg (T.W.).
Declarations
Conflict of interest
D. W. received honoraria from Mallinckrodt, Novartis, Takeda, MACO, and Neovii.
The authors declare that they have no conflict of interest.
Informed consent
Informed consent was obtained from all patients for being included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Matthias Fante and Daniel Wolff contributed equally to this work. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33515310 | 18,904,824 | 2021-03 |
What was the outcome of reaction 'Bacterial sepsis'? | Abatacept as salvage therapy in chronic graft-versus-host disease-a retrospective analysis.
The immunomodulatory fusion protein abatacept has recently been investigated for the treatment of steroid-refractory chronic graft-versus-host disease (cGvHD) in a phase 1 clinical trial. We analyzed the safety and efficacy of abatacept for cGvHD therapy in a retrospective study with 15 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received abatacept for cGvHD with a median age of 49 years. Grading was performed as part of the clinical routine according to the National Institute of Health's (NIH) consensus criteria at initiation of abatacept and 1, 3, 6, 9 and 12 months thereafter. The median time of follow-up was 191 days (range 55-393 days). Best overall response rate (ORR) was 40%. In particular, patients with bronchiolitis obliterans syndrome showed significant clinical improvement and durable responses following abatacept treatment with a response rate of 89% based on improvement in lung severity score (n = 6) or stabilized lung function (n = 4) or both (n = 3). Infectious complications CTCAE °III or higher were observed in 3/15 patients. None of the patients relapsed from the underlying malignancy. Thus, abatacept appears to be a promising treatment option for cGvHD, in particular for patients with lung involvement. However, further evaluation within a phase 2 clinical trial is required.
Introduction
While allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established, potentially curative therapy for several malignant and benign hematologic diseases, chronic graft-versus-host disease (cGvHD) remains a major complication after allo-HSCT. cGvHD occurs in up to 70% of patients after allo-HSCT and significantly contributes to impaired quality of life and non-relapse mortality (NRM)/transplant-related mortality (TRM) [1–5].
Corticosteroids represent the backbone of cGVHD treatment, but contribute to an already high morbidity and mortality by causing complications such as osteoporosis, myopathy, avascular necrosis, and glaucoma [3, 6]. A substantial number of patients does not respond to corticosteroids alone and require second-line therapy with the recently FDA-approved Bruton’s tyrosine kinase inhibitor ibrutinib or extracorporeal photopheresis [5, 7–9]. Further treatment options are usually based on retrospective or phase 1/2 clinical studies and show limited efficacy in a significant proportion of patients despite harboring the risk of toxicity including infectious complications [10–14].
Abatacept is a novel, first in class immunomodulatory drug exerting its effect by costimulatory blockade and is applied for the treatment of rheumatoid arthritis and other rheumatological diseases [15–17]. It is a recombinant fusion protein comprised of the extracellular domain of the immune checkpoint protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4) fused to the Fc fragment of IgG1 [18]. By binding with high affinity to the costimulatory receptors CD80 and CD86 on antigen presenting cells (APCs), it counteracts the costimulatory signal mediated by the ligand CD28, which is required for full T cell activation [19].
The highly complex pathophysiology of cGvHD is still poorly understood. Apart from alloreactive donor T cell responses, it involves aberrant innate immune signaling, endothelial cell injury, dysfunctional central tolerance induction (due to thymic damage as a result of the conditioning regimen or alloreactive T cells), insufficient de novo development of regulatory T cells (Treg), dysregulation of B cells, and cytokine signaling eventually resulting in chronic inflammation and fibrotic remodeling [20–22].
Since cGvHD is at least in part mediated by host reactive T cells stimulated by allogeneic antigens [23], there is high rationale for abatacept as a treatment option in cGvHD, and it has been reported that CTLA-4 blockade can prevent aGvHD and cGvHD and even reverse cGvHD in murine models [24]. Recently, abatacept has received breakthrough approval by the American Food and Drug Administration (FDA) for the prevention of acute GvHD and has shown efficacy in a phase 1 clinical trial for patients with steroid-refractory cGvHD, albeit with relatively low patient numbers [25].
Therefore, we analyzed the efficacy and safety of abatacept for the treatment of advanced cGvHD in a multicentric retrospective study.
Patients and methods
Patients
In this retrospective analysis, patients treated with abatacept for cGvHD between 2018 and 2020 at the University Hospital Regensburg (Germany), University Hospital Giessen and Marburg (Germany), University Hospital and Karolinska Institutet (Stockholm, Sweden) and University Hospital La Paz (Madrid, Spain) were included into the analysis approved by the institutional ethics review board (no.19-1586-104). Documentation of cGvHD was performed as part of clinical routine using the diagnosis and response criteria according to the National Institute of Health (NIH) consensus guidelines [26]. No new immunosuppressive agent was applied within at least 4 weeks before abatacept therapy, and response assessment was discontinued upon requirement of any additional immunosuppressive treatment post abatacept therapy. Patients received abatacept intravenously at a dose of 10 mg/kg body weight (maximum 800 mg) every 2 weeks for the first three doses and then every 4 weeks.
Definition of abatacept response and adverse events
Response to abatacept was assessed at 1, 3, 6, 9, and 12 months after start of therapy. In case of treatment with an additional immunosuppressive agent, the last response assessment for abatacept was performed at onset of new therapy. Last follow-up of the present analysis was January 2020. Complete remission (CR) was defined as resolution of all organ manifestations of cGvHD. Improvement of at least one organ grade without progression of cGvHD at other organs was classified as partial response (PR); mixed response was defined as simultaneous improvement in one organ and progression in another organ. Patients who showed no change in organ grading were classified as stable disease (SD). Failure-free survival (FFS) was defined as absence of relapse or non-relapse mortality or addition of further systemic therapy. Overall response rates (ORR) were calculated based on intention to treat analysis. Infectious complications were assessed and classified according to the common terminology criteria for adverse events version 5.0 (CTCAE 5.0) with toxicities captured in the analysis starting from grade III.
Results
Patient characteristics
We treated 15 patients with abatacept for cGvHD at our centers between 2018 and 2020. Among those patients, the diagnoses leading to allo-HSCT were myeloid disorders (acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasia (MPN)) in 10 patients, lymphatic malignancies (acute lymphoblastic leukemia (ALL), and Hodgkin lymphoma (HL)) in four patients and one patient suffering from CTLA-4 haploinsufficiency.
All patients had received peripheral blood stem cells (PBSC) as graft source with 11 patients grafted from an HLA-matched sibling (5 patients) or an unrelated donor (8 patients). HLA-matched donors were defined as 10/10 match. One patient had received an HLA-C mismatched graft from an unrelated donor, and one patient received a haploidentical graft from a related donor. Acute GvHD grade II or higher according to Glucksberg criteria occurred in 11 patients (85%). cGvHD onset was quiescent in 8 patients, de novo in three patients and progressive in four patients. Most of the patients (n = 12; 80%), who received abatacept, had severe cGvHD. One patient included in the analysis had mild cGvHD (prior history of moderate cGvHD) and received abatacept due to intolerance to other immunosuppressive agents. One patient was treated for autoimmune-hemolytic anemia (AIHA) refractory to corticosteroids and rituximab not fulfilling the NIH criteria for cGvHD falling in the category “undefined other cGvHD” [26, 27]. The majority of the patients had steroid dependent cGvHD (n = 10, 67%, all others steroid-refractory cGvHD (n = 5; 33%)). A platelet count < 100/nl was observed in 4 patients (27%) at the time of abatacept initiation.
The most common organ manifestations of cGvHD were skin (n = 11; 73%), lung (n = 11; 73%), eyes (n = 10; 67%), and oral cavity (n = 10; 67%). Abatacept was initiated on median day 1848 (range 432–7953) after allo-HSCT and on day 1592 (range 28–7864) after cGvHD onset, respectively. The corticosteroid dose at abatacept initiation was 0.34 mg/kg in median (range 0,12–2 mg/kg). The patients included in the analysis had received a median of 4.6 prior treatment lines (range 2–5) for cGvHD. Within 3 months before abatacept treatment was started, most patients did not undergo new immunosuppressive treatments (80%). The remaining patients (20%), who underwent new immunosuppressive treatments within 3 months, were progressive or refractory to the initiated treatment.
Median follow-up after treatment was 179 days (range 55–393). Patient characteristics including age, gender, diagnosis, donor type, stem cell source, conditioning regimen, GvHD prophylaxis, history of acute GvHD, and chronic GvHD are shown in Table 1.Table 1 Patient characteristics
Patient characteristics Value
Patients 15
Female, n (%) 10
Male, n (%) 5
Age, median (range)* 49 (5–70)
Diagnosis
AML, n (%) 7 (47)
ALL, n (%) 2 (13)
MPN (%) 3 (15)
Others, n (%) 3 (15)
Donor type
HLA-matched unrelated, n (%) 7 (47)
HLA-mismatched unrelated, n (%) 1 (7)
HLA-matched related, n (%) 6 (40)
HLA-mismatched related, n (%) 0
Haploidentical related, n (%) 1 (7)
Sex mismatch: female to male
Yes, n (%) 1 (7)
No, n (%) 14 (93)
Stem cell source
Peripheral blood stem cells, n (%) 14 (93)
Bone marrow, n (%) 1 (7)
GvHD prophylaxis
ATG/CsA/MTX, n (%) 3 (20)
CsA/MTX, n (%) 5 (33)
CsA/MMF, n (%) 1 (7)
Other 6 (40)
History of aGvHD
Grades 0–I, n (%) 4 (27)
Grades II–IV, n (%) 11 (73)
Characteristics Value
Onset of cGvHD after allo-SCT, median days (range) 256 (76–597)
Time point of abatacept treatment after allo-SCT, median days, (range) 1848 (432–7953)
Time point of abatacept treatment after cGvHD onset, median days, (range) 1592 (133–7864)
Age at abatacept initiation, median (range) 49 (5–70)
Number of abatacept doses, median (range) 7.1 (1–20)
cGvHD, n (%)
Mild 1 (7)
Moderate 0
Severe
non-NIH defined (AIHA)
13 (87)
1 (7)
Steroid response of cGvHD
Steroid resistance 5 (33)
Steroid dependence 10 (67)
Number of organ involvement of cGvHD, n (%)
One 1 (7)
Two 1 (7)
Three 5 (33)
Four or more 8 (53)
Type of cGvHD organ involvement, n (%)
Skin 11 (73)
Oral 10 (67)
Eyes 10 (67)
Liver 2 (13)
Gut 4 (27)
Lung 11 (73)
Musculoskeletal 7 (47)
Genital 2 (13)
AIHA 1 (7)
ISM at the beginning of abatacept, n (%)
No ISM 0
One ISM 5 (33)
Two ISM 8 (53)
Three or more ISM 2 (13)
Number of prior therapies before abatacept, n (%)
One 2 (13)
Two 2 13)
Three 1 (7)
Four or more prior therapies 10 (67)
New ISM within 3 months before abatacept, n (%)
Yes 3 (20)
No 12 (80)
n number of patients, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, MPN myeloproliferative neoplasia, HLA human leukocyte antigen, ATG anti-thymocyte globulin, CsA ciclosporin A, MTX methotrexate, MMF mycophenolate mofetil, GvHD graft-versus-host disease, aGvHD acute GvHD, cGvHD chronic GvHD, ISM immunosuppressive medication
Response to abatacept
Response to abatacept treatment is illustrated in Fig. 1 and Table 2 at the different time points of this analysis.Fig. 1 Clinical course during abatacept treatment
Table 2 Duration of abatacept treatment and clinical course
Patient # Day of start IS at start # of doses Organ involvement (grade) at start Skin features at start 1 m RR 2 m RR 3 m RR 6 m RR 9 m RR 12 m RR Follow up
1 7953 GC, E, MMF 7 s (0), e (3), m (0), f (0), lu (3) - SD SD SD SD - - Stabilized lung function, abatacept discontinued due to prolonged fatigue and diarrhea after administration
2 1596 GC, Rux 6 s (3), e (1), m (1), f (2), lu (2) S PR PR PR - - - Improvement of lung GvHD, new IS with ibrutinib and tocilizumab after 6 months
3 3261 GC, CsA 2 s (3), e (0), m (2), f (2), lu (0) S SD SD SD SD - - New IS with daratumumab after no improvement of oral ulcers
4 1425 GC 4 s (3), e (1), m (1), f (2), lu (2) S SD MR SD - - - Death due to aortic valve rupture (preexisting aortic valve insufficiency)
5 949 GC, Rux 3 s (3), e (2), m (0), f (2), lu (0) S SD SD - - - - New IS with Treg after 2 months
6 722 GC 10 s (0), e (3), m (0), f (0), lu (3) - PR PR PR PR - - Stabilized lung GvHD and improved functional capacity, death due to sepsis 9 months after abatacept start
7 1318 GC 1 s (0), e (0), m (1), f (0), lu (0) - PR PR - - - - Abatacept was given due to intolerance to IS agents and multiple infectious complications; death due to infectious complications of PAD
8 4587 GC, Bari 5 s (3), e (0), m (0), f (2), lu (0) S SD SD SD - - - New IS with tofacitinib after persisting arthralgia
9* 1311 GC, Ima 14 s (1), e (1), m (1), gi (1), f (0), lu (3) L PR PR PR PR PR PR Durable improvement of lung and skin GvHD. Less oxygen demand, reduced coughing
10* 432 GC, E 14 s (3), e (1), m (1), f (0), lu (0) S SD SD PR PR PR PR Improvement of ocular GvHD
11 1162 GC, Tac 9 s (1), e (3), m (1), f (0), lu (3) L MR MR MR MR - - Stabilized lung function, progressive oral affection, new IS with ruxolitinib after 9 months
12* 517 Toc 13 s (2), m (1), gi (1), li (1), f (0), lu (3) L PR PR PR PR PR PR Complete resolution of s, m, gi and li GvHD. Significant improvement of lung GvHD (reduction from grades 3 to 1)
13* 157 GC 4 AIHA - CR CR CR CR NR NR Complete resolution of AIHA
14* 469 GC, Ibru s (0), e (0), m (1), gi (0), f (0), lu (1) - SD SD SD NR NR NR Stabilized lung function
15* 1864 CsA 10 s (1), e (1), m (2), gi (0), f (2), lu (3) L SD PR PR PR PR NR Increased mobility and improved lung symptoms
Median 1848 7
1/3/6/9/12-month RR 1/3/6/12-month response rate, respectively; GC glucocorticoid; E everolimus; MMF mycophenolate mofetil; Rux ruxolitinib; CsA cyclosporine A; Bari baricitinib; Ima imatinib; Tac tacrolimus; Toc tocilizumab; Ibru ibrutinib; s skin; e eyes; m mouth; f fascia; lu lungs; ge genital; S sclerotic features; L lichen planus-like features; PD progressive disease; SD stable disease; PR partial response; MR mixed response; NR not reached; Treg regulatory T cells; IS immunosuppression; PAD peripheral artery disease; QOL quality of life; AIHA autoimmune hemolytic anemia; *ongoing therapy
Response to abatacept at 1 month
One month after first administration of abatacept, the patient (7%) with AIHA showed CR, 5 (33%) patients had PR, one patient (7%) showed MR with improved lung function but progressive oral affection, and 8 patients (53%) presented with SD. None of the patients required start of an additional immunosuppressive therapy. The overall response rate (ORR) at 1 month was 40%, and failure-free survival (FFS) was 100%.
Response to abatacept at 3 months
At 3 months after start of abatacept therapy, one patient showed CR (7%), 5 (33%) patients had PR, one patient showed MR (7%), and 6 patients (40%) had SD. One patient who had SD started a new immunosuppression and another patient with a PR succumbed to infectious complications of severe peripheral artery disease unrelated to abatacept. ORR at 3 months was therefore 40% with an FFS of 87%.
Response to abatacept at 6 and 9 months
The 6 months follow-up was reached by nine patients with one patient remaining in CR (7%), four patients achieving PR (27%), one MR (7%) with sustained stabilized lung function but impaired oral affection, and two patients with SD (13%). At termination of our analysis, one patient was still treated with abatacept but has not reached the 6 months follow-up yet. One patient with PR started a new IS with ibrutinib and tocilizumab, and another patient who was in SD discontinued abatacept and was switched to tofacitinib due to persisting arthralgia. One highly comorbid patient with preexisting aortic valve insufficiency died due to aortic valve rupture. Thus, the ORR at 6 months was 33% with an FFS of 64%.
Nine months after initiation of abatacept treatment, four patients still received therapy and two patients currently still receiving abatacept have not reached the time point yet. Of the remaining patients, three showed a PR (20%), one patient discontinued abatacept due to sustained and not improved oral ulcers, and another patient died due to urosepsis, displaying an ORR of 23% with an FFS of 31%.
Response to abatacept at 12 months
At 12 months, three patients were still treated with abatacept, and three who currently receive abatacept therapy have not reached the time point yet. Three patients still had PR (25%) resulting in an ORR of 25% with FFS of 25%.
Response in patients with lung involvement of cGvHD
Interestingly, we observed that patients with lung involvement (n = 9) particularly benefitted from therapy with abatacept with an overall response rate of 89% based on improvement in lung severity score (n = 6), lung function as measured by FEV1 in Fig. 1 (n = 4) or both (n = 3). Of note, although only a stabilization on abatacept was achieved, they experienced prior constant loss of FEV1 as shown in Fig. 1. Of note, all patients received in parallel therapy with FAM (fluticasone, azithromycine, montelukast) partly in combination with beta-agonists which had already been applied > 1 month before abatacept initiation without response (Fig. 2).Fig. 2 Forced expiratory volume % before and during abatacept therapy
Infectious and other complications during abatacept
Adverse events (AE) and serious adverse events (SAE) during abatacept treatment are illustrated in Table 3. In general, abatacept administration was well tolerated; however, one patient repeatedly showed nausea, vomiting, diarrhea, fever, and fatigue for several days repeatedly upon infusion leading to termination of treatment after 7 applications. Another patient showed alopecia during treatment. Three of the patients included in the analysis developed significant infectious complications requiring hospital admission with one highly comorbid patient succumbing to urosepsis, and another patient already mentioned died due to infectious complications associated with severe peripheral artery disease unrelated to cGvHD.Table 3 Adverse and serious adverse events of abatacept treatment
Patient # AE SAE Specification
1 Yes No Fatigue, diarrhea, fever
2 No Yes Death due to gram-negative sepsis 70 days after last abatacept dose
3 No No -
4 No No -
5 No No -
6 No Yes Death due to urosepsis 24 days after last abatacept dose
7 No Yes Death due to infectious complications of peripheral artery disease
8 No No -
9 No No -
10 Yes No Alopecia after abatacept initiation
11 No No -
12 No Yes Hospital admission due to influenza A pneumonia
13 No No -
14 No No -
15 Yes No Bone pain after infusion
Discussion
cGvHD occurs with an incidence of 30–70% in patients undergoing allo-HSCT [21], and as it reduces quality of life and significantly contributes to NRM/TRM, there is still a high clinical need for effective second-line treatments [28, 29]. The underlying complex pathophysiology of cGvHD involves both B and T cell immunity and results in pleiotropic clinical manifestations resembling various autoimmune diseases [21]. Due to the involvement of auto- und alloreactive T cells in the development and course of cGvHD, there is high rationale for the use of costimulation blockade via the CTLA-4 pathway [20]. The introduction of the immunomodulatory drug abatacept has significantly improved the therapy for rheumatoid arthritis patients not responding sufficiently to conventional disease modifying antirheumatic drugs and has in this context shown efficacy and improvement of quality of life [19, 30, 31]. Based on observations in preclinical models, abatacept has been tested in combination with a CD25 monoclonal antibody in pediatric recipients of haploidentical allo-HSCT for the treatment of hyperacute GvHD, where it has shown efficacy [32]. Moreover, the safety and efficacy of abatacept for the prevention of aGvHD and treatment of SR-cGvHD were recently evaluated with promising results in phase 1 clinical trials [25, 33], and subsequent randomized phase 2 trials have been initiated (NCT0174313; NCT01954979).
In this retrospective analysis of cGvHD patients treated with abatacept at four centers, we observed a best overall response rate of 40%, which is comparable to the clinical response rate of 44% recently reported by Nahas et al. [25]. Despite the low number of patients and the retrospective character of the analysis, we observed that in particular patients with bronchiolitis obliterans syndrome (BOS) showed substantial clinical improvement after abatacept application with durable responses, stabilized lung function (Fig. 1), albeit this was not reflected by an improvement in lung grading in all patients. Given the frequently irreversible character of lung involvement due to fibrotic remodeling, we consider clinical improvement, lowering of oxygen demand, and stabilized lung function as relevant response parameters, especially in our patient cohort with mostly severe cGVHD [34]. Interestingly, it has been reported for several autoimmune diseases that costimulation blockade of the CTLA-4 axis selectively decreases the proportion of T follicular helper cells, thereby reducing T cell help for germinal center B cells [35–37]. Given that BOS is explicitly characterized by disturbance of B cell homeostasis with increased CD19+CD21- B cells and excess of B cell activation factor (BAFF) [38], abatacept might target Tfh cells in this context, which would at least partially explain the particular improvement of patients with BOS in our study. In addition, we observed a complete response in a steroid and rituximab refractory AIHA patient as previously described [39]. Despite not meeting NIH diagnostic criteria for cGvHD, we included this patient in our analysis since it has recently been reported that based on biomarker profiles, patients with signs of immune mediated damage not diagnostic for cGvHD do not significantly differ from those showing diagnostic signs of cGvHD suggesting that the current NIH diagnostic criteria may not involve all targets of cGvHD [40, 41]. Noteworthy, in the phase 1 clinical trial reported by Nahas et al., a reduction of corticosteroid usage of 51.3% was reported, while the authors state that this effect might have been overestimated due to the not blinded or randomized design of the study. In this regard, we did not observe consistent steroid reduction in patients responding to abatacept, yet most of our patients received a relatively low corticosteroid dose at start of abatacept. Interestingly, it has been reported in a preclinical model of chronic lung allograft dysfunction that bronchiolitis obliterans can be attenuated by CTLA-4-Ig administration presumably by promoting LAG3+Treg mediated anti-inflammatory effects providing a potential mechanistic explanation for the observed clinical response [42]. Of note, progression of cGvHD within three months was indicative for treatment failure, and all patients, who achieved at least a PR, were responding in the first three months. Thus, based on our experience, we would suggest discontinuing abatacept treatment, if patients do not show a response within this period. Overall, abatacept seems to be a relevant treatment option for patients with cGvHD, particularly for patients with BOS, but this has to be further investigated in future clinical trials.
Funding
Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projekt-ID 324392634 - TRR221, subproject B10 (D.W.), and by the ReForM program of the University of Regensburg (T.W.).
Declarations
Conflict of interest
D. W. received honoraria from Mallinckrodt, Novartis, Takeda, MACO, and Neovii.
The authors declare that they have no conflict of interest.
Informed consent
Informed consent was obtained from all patients for being included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Matthias Fante and Daniel Wolff contributed equally to this work. | Fatal | ReactionOutcome | CC BY | 33515310 | 18,904,824 | 2021-03 |
What was the outcome of reaction 'Infection'? | Abatacept as salvage therapy in chronic graft-versus-host disease-a retrospective analysis.
The immunomodulatory fusion protein abatacept has recently been investigated for the treatment of steroid-refractory chronic graft-versus-host disease (cGvHD) in a phase 1 clinical trial. We analyzed the safety and efficacy of abatacept for cGvHD therapy in a retrospective study with 15 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received abatacept for cGvHD with a median age of 49 years. Grading was performed as part of the clinical routine according to the National Institute of Health's (NIH) consensus criteria at initiation of abatacept and 1, 3, 6, 9 and 12 months thereafter. The median time of follow-up was 191 days (range 55-393 days). Best overall response rate (ORR) was 40%. In particular, patients with bronchiolitis obliterans syndrome showed significant clinical improvement and durable responses following abatacept treatment with a response rate of 89% based on improvement in lung severity score (n = 6) or stabilized lung function (n = 4) or both (n = 3). Infectious complications CTCAE °III or higher were observed in 3/15 patients. None of the patients relapsed from the underlying malignancy. Thus, abatacept appears to be a promising treatment option for cGvHD, in particular for patients with lung involvement. However, further evaluation within a phase 2 clinical trial is required.
Introduction
While allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established, potentially curative therapy for several malignant and benign hematologic diseases, chronic graft-versus-host disease (cGvHD) remains a major complication after allo-HSCT. cGvHD occurs in up to 70% of patients after allo-HSCT and significantly contributes to impaired quality of life and non-relapse mortality (NRM)/transplant-related mortality (TRM) [1–5].
Corticosteroids represent the backbone of cGVHD treatment, but contribute to an already high morbidity and mortality by causing complications such as osteoporosis, myopathy, avascular necrosis, and glaucoma [3, 6]. A substantial number of patients does not respond to corticosteroids alone and require second-line therapy with the recently FDA-approved Bruton’s tyrosine kinase inhibitor ibrutinib or extracorporeal photopheresis [5, 7–9]. Further treatment options are usually based on retrospective or phase 1/2 clinical studies and show limited efficacy in a significant proportion of patients despite harboring the risk of toxicity including infectious complications [10–14].
Abatacept is a novel, first in class immunomodulatory drug exerting its effect by costimulatory blockade and is applied for the treatment of rheumatoid arthritis and other rheumatological diseases [15–17]. It is a recombinant fusion protein comprised of the extracellular domain of the immune checkpoint protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4) fused to the Fc fragment of IgG1 [18]. By binding with high affinity to the costimulatory receptors CD80 and CD86 on antigen presenting cells (APCs), it counteracts the costimulatory signal mediated by the ligand CD28, which is required for full T cell activation [19].
The highly complex pathophysiology of cGvHD is still poorly understood. Apart from alloreactive donor T cell responses, it involves aberrant innate immune signaling, endothelial cell injury, dysfunctional central tolerance induction (due to thymic damage as a result of the conditioning regimen or alloreactive T cells), insufficient de novo development of regulatory T cells (Treg), dysregulation of B cells, and cytokine signaling eventually resulting in chronic inflammation and fibrotic remodeling [20–22].
Since cGvHD is at least in part mediated by host reactive T cells stimulated by allogeneic antigens [23], there is high rationale for abatacept as a treatment option in cGvHD, and it has been reported that CTLA-4 blockade can prevent aGvHD and cGvHD and even reverse cGvHD in murine models [24]. Recently, abatacept has received breakthrough approval by the American Food and Drug Administration (FDA) for the prevention of acute GvHD and has shown efficacy in a phase 1 clinical trial for patients with steroid-refractory cGvHD, albeit with relatively low patient numbers [25].
Therefore, we analyzed the efficacy and safety of abatacept for the treatment of advanced cGvHD in a multicentric retrospective study.
Patients and methods
Patients
In this retrospective analysis, patients treated with abatacept for cGvHD between 2018 and 2020 at the University Hospital Regensburg (Germany), University Hospital Giessen and Marburg (Germany), University Hospital and Karolinska Institutet (Stockholm, Sweden) and University Hospital La Paz (Madrid, Spain) were included into the analysis approved by the institutional ethics review board (no.19-1586-104). Documentation of cGvHD was performed as part of clinical routine using the diagnosis and response criteria according to the National Institute of Health (NIH) consensus guidelines [26]. No new immunosuppressive agent was applied within at least 4 weeks before abatacept therapy, and response assessment was discontinued upon requirement of any additional immunosuppressive treatment post abatacept therapy. Patients received abatacept intravenously at a dose of 10 mg/kg body weight (maximum 800 mg) every 2 weeks for the first three doses and then every 4 weeks.
Definition of abatacept response and adverse events
Response to abatacept was assessed at 1, 3, 6, 9, and 12 months after start of therapy. In case of treatment with an additional immunosuppressive agent, the last response assessment for abatacept was performed at onset of new therapy. Last follow-up of the present analysis was January 2020. Complete remission (CR) was defined as resolution of all organ manifestations of cGvHD. Improvement of at least one organ grade without progression of cGvHD at other organs was classified as partial response (PR); mixed response was defined as simultaneous improvement in one organ and progression in another organ. Patients who showed no change in organ grading were classified as stable disease (SD). Failure-free survival (FFS) was defined as absence of relapse or non-relapse mortality or addition of further systemic therapy. Overall response rates (ORR) were calculated based on intention to treat analysis. Infectious complications were assessed and classified according to the common terminology criteria for adverse events version 5.0 (CTCAE 5.0) with toxicities captured in the analysis starting from grade III.
Results
Patient characteristics
We treated 15 patients with abatacept for cGvHD at our centers between 2018 and 2020. Among those patients, the diagnoses leading to allo-HSCT were myeloid disorders (acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasia (MPN)) in 10 patients, lymphatic malignancies (acute lymphoblastic leukemia (ALL), and Hodgkin lymphoma (HL)) in four patients and one patient suffering from CTLA-4 haploinsufficiency.
All patients had received peripheral blood stem cells (PBSC) as graft source with 11 patients grafted from an HLA-matched sibling (5 patients) or an unrelated donor (8 patients). HLA-matched donors were defined as 10/10 match. One patient had received an HLA-C mismatched graft from an unrelated donor, and one patient received a haploidentical graft from a related donor. Acute GvHD grade II or higher according to Glucksberg criteria occurred in 11 patients (85%). cGvHD onset was quiescent in 8 patients, de novo in three patients and progressive in four patients. Most of the patients (n = 12; 80%), who received abatacept, had severe cGvHD. One patient included in the analysis had mild cGvHD (prior history of moderate cGvHD) and received abatacept due to intolerance to other immunosuppressive agents. One patient was treated for autoimmune-hemolytic anemia (AIHA) refractory to corticosteroids and rituximab not fulfilling the NIH criteria for cGvHD falling in the category “undefined other cGvHD” [26, 27]. The majority of the patients had steroid dependent cGvHD (n = 10, 67%, all others steroid-refractory cGvHD (n = 5; 33%)). A platelet count < 100/nl was observed in 4 patients (27%) at the time of abatacept initiation.
The most common organ manifestations of cGvHD were skin (n = 11; 73%), lung (n = 11; 73%), eyes (n = 10; 67%), and oral cavity (n = 10; 67%). Abatacept was initiated on median day 1848 (range 432–7953) after allo-HSCT and on day 1592 (range 28–7864) after cGvHD onset, respectively. The corticosteroid dose at abatacept initiation was 0.34 mg/kg in median (range 0,12–2 mg/kg). The patients included in the analysis had received a median of 4.6 prior treatment lines (range 2–5) for cGvHD. Within 3 months before abatacept treatment was started, most patients did not undergo new immunosuppressive treatments (80%). The remaining patients (20%), who underwent new immunosuppressive treatments within 3 months, were progressive or refractory to the initiated treatment.
Median follow-up after treatment was 179 days (range 55–393). Patient characteristics including age, gender, diagnosis, donor type, stem cell source, conditioning regimen, GvHD prophylaxis, history of acute GvHD, and chronic GvHD are shown in Table 1.Table 1 Patient characteristics
Patient characteristics Value
Patients 15
Female, n (%) 10
Male, n (%) 5
Age, median (range)* 49 (5–70)
Diagnosis
AML, n (%) 7 (47)
ALL, n (%) 2 (13)
MPN (%) 3 (15)
Others, n (%) 3 (15)
Donor type
HLA-matched unrelated, n (%) 7 (47)
HLA-mismatched unrelated, n (%) 1 (7)
HLA-matched related, n (%) 6 (40)
HLA-mismatched related, n (%) 0
Haploidentical related, n (%) 1 (7)
Sex mismatch: female to male
Yes, n (%) 1 (7)
No, n (%) 14 (93)
Stem cell source
Peripheral blood stem cells, n (%) 14 (93)
Bone marrow, n (%) 1 (7)
GvHD prophylaxis
ATG/CsA/MTX, n (%) 3 (20)
CsA/MTX, n (%) 5 (33)
CsA/MMF, n (%) 1 (7)
Other 6 (40)
History of aGvHD
Grades 0–I, n (%) 4 (27)
Grades II–IV, n (%) 11 (73)
Characteristics Value
Onset of cGvHD after allo-SCT, median days (range) 256 (76–597)
Time point of abatacept treatment after allo-SCT, median days, (range) 1848 (432–7953)
Time point of abatacept treatment after cGvHD onset, median days, (range) 1592 (133–7864)
Age at abatacept initiation, median (range) 49 (5–70)
Number of abatacept doses, median (range) 7.1 (1–20)
cGvHD, n (%)
Mild 1 (7)
Moderate 0
Severe
non-NIH defined (AIHA)
13 (87)
1 (7)
Steroid response of cGvHD
Steroid resistance 5 (33)
Steroid dependence 10 (67)
Number of organ involvement of cGvHD, n (%)
One 1 (7)
Two 1 (7)
Three 5 (33)
Four or more 8 (53)
Type of cGvHD organ involvement, n (%)
Skin 11 (73)
Oral 10 (67)
Eyes 10 (67)
Liver 2 (13)
Gut 4 (27)
Lung 11 (73)
Musculoskeletal 7 (47)
Genital 2 (13)
AIHA 1 (7)
ISM at the beginning of abatacept, n (%)
No ISM 0
One ISM 5 (33)
Two ISM 8 (53)
Three or more ISM 2 (13)
Number of prior therapies before abatacept, n (%)
One 2 (13)
Two 2 13)
Three 1 (7)
Four or more prior therapies 10 (67)
New ISM within 3 months before abatacept, n (%)
Yes 3 (20)
No 12 (80)
n number of patients, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, MPN myeloproliferative neoplasia, HLA human leukocyte antigen, ATG anti-thymocyte globulin, CsA ciclosporin A, MTX methotrexate, MMF mycophenolate mofetil, GvHD graft-versus-host disease, aGvHD acute GvHD, cGvHD chronic GvHD, ISM immunosuppressive medication
Response to abatacept
Response to abatacept treatment is illustrated in Fig. 1 and Table 2 at the different time points of this analysis.Fig. 1 Clinical course during abatacept treatment
Table 2 Duration of abatacept treatment and clinical course
Patient # Day of start IS at start # of doses Organ involvement (grade) at start Skin features at start 1 m RR 2 m RR 3 m RR 6 m RR 9 m RR 12 m RR Follow up
1 7953 GC, E, MMF 7 s (0), e (3), m (0), f (0), lu (3) - SD SD SD SD - - Stabilized lung function, abatacept discontinued due to prolonged fatigue and diarrhea after administration
2 1596 GC, Rux 6 s (3), e (1), m (1), f (2), lu (2) S PR PR PR - - - Improvement of lung GvHD, new IS with ibrutinib and tocilizumab after 6 months
3 3261 GC, CsA 2 s (3), e (0), m (2), f (2), lu (0) S SD SD SD SD - - New IS with daratumumab after no improvement of oral ulcers
4 1425 GC 4 s (3), e (1), m (1), f (2), lu (2) S SD MR SD - - - Death due to aortic valve rupture (preexisting aortic valve insufficiency)
5 949 GC, Rux 3 s (3), e (2), m (0), f (2), lu (0) S SD SD - - - - New IS with Treg after 2 months
6 722 GC 10 s (0), e (3), m (0), f (0), lu (3) - PR PR PR PR - - Stabilized lung GvHD and improved functional capacity, death due to sepsis 9 months after abatacept start
7 1318 GC 1 s (0), e (0), m (1), f (0), lu (0) - PR PR - - - - Abatacept was given due to intolerance to IS agents and multiple infectious complications; death due to infectious complications of PAD
8 4587 GC, Bari 5 s (3), e (0), m (0), f (2), lu (0) S SD SD SD - - - New IS with tofacitinib after persisting arthralgia
9* 1311 GC, Ima 14 s (1), e (1), m (1), gi (1), f (0), lu (3) L PR PR PR PR PR PR Durable improvement of lung and skin GvHD. Less oxygen demand, reduced coughing
10* 432 GC, E 14 s (3), e (1), m (1), f (0), lu (0) S SD SD PR PR PR PR Improvement of ocular GvHD
11 1162 GC, Tac 9 s (1), e (3), m (1), f (0), lu (3) L MR MR MR MR - - Stabilized lung function, progressive oral affection, new IS with ruxolitinib after 9 months
12* 517 Toc 13 s (2), m (1), gi (1), li (1), f (0), lu (3) L PR PR PR PR PR PR Complete resolution of s, m, gi and li GvHD. Significant improvement of lung GvHD (reduction from grades 3 to 1)
13* 157 GC 4 AIHA - CR CR CR CR NR NR Complete resolution of AIHA
14* 469 GC, Ibru s (0), e (0), m (1), gi (0), f (0), lu (1) - SD SD SD NR NR NR Stabilized lung function
15* 1864 CsA 10 s (1), e (1), m (2), gi (0), f (2), lu (3) L SD PR PR PR PR NR Increased mobility and improved lung symptoms
Median 1848 7
1/3/6/9/12-month RR 1/3/6/12-month response rate, respectively; GC glucocorticoid; E everolimus; MMF mycophenolate mofetil; Rux ruxolitinib; CsA cyclosporine A; Bari baricitinib; Ima imatinib; Tac tacrolimus; Toc tocilizumab; Ibru ibrutinib; s skin; e eyes; m mouth; f fascia; lu lungs; ge genital; S sclerotic features; L lichen planus-like features; PD progressive disease; SD stable disease; PR partial response; MR mixed response; NR not reached; Treg regulatory T cells; IS immunosuppression; PAD peripheral artery disease; QOL quality of life; AIHA autoimmune hemolytic anemia; *ongoing therapy
Response to abatacept at 1 month
One month after first administration of abatacept, the patient (7%) with AIHA showed CR, 5 (33%) patients had PR, one patient (7%) showed MR with improved lung function but progressive oral affection, and 8 patients (53%) presented with SD. None of the patients required start of an additional immunosuppressive therapy. The overall response rate (ORR) at 1 month was 40%, and failure-free survival (FFS) was 100%.
Response to abatacept at 3 months
At 3 months after start of abatacept therapy, one patient showed CR (7%), 5 (33%) patients had PR, one patient showed MR (7%), and 6 patients (40%) had SD. One patient who had SD started a new immunosuppression and another patient with a PR succumbed to infectious complications of severe peripheral artery disease unrelated to abatacept. ORR at 3 months was therefore 40% with an FFS of 87%.
Response to abatacept at 6 and 9 months
The 6 months follow-up was reached by nine patients with one patient remaining in CR (7%), four patients achieving PR (27%), one MR (7%) with sustained stabilized lung function but impaired oral affection, and two patients with SD (13%). At termination of our analysis, one patient was still treated with abatacept but has not reached the 6 months follow-up yet. One patient with PR started a new IS with ibrutinib and tocilizumab, and another patient who was in SD discontinued abatacept and was switched to tofacitinib due to persisting arthralgia. One highly comorbid patient with preexisting aortic valve insufficiency died due to aortic valve rupture. Thus, the ORR at 6 months was 33% with an FFS of 64%.
Nine months after initiation of abatacept treatment, four patients still received therapy and two patients currently still receiving abatacept have not reached the time point yet. Of the remaining patients, three showed a PR (20%), one patient discontinued abatacept due to sustained and not improved oral ulcers, and another patient died due to urosepsis, displaying an ORR of 23% with an FFS of 31%.
Response to abatacept at 12 months
At 12 months, three patients were still treated with abatacept, and three who currently receive abatacept therapy have not reached the time point yet. Three patients still had PR (25%) resulting in an ORR of 25% with FFS of 25%.
Response in patients with lung involvement of cGvHD
Interestingly, we observed that patients with lung involvement (n = 9) particularly benefitted from therapy with abatacept with an overall response rate of 89% based on improvement in lung severity score (n = 6), lung function as measured by FEV1 in Fig. 1 (n = 4) or both (n = 3). Of note, although only a stabilization on abatacept was achieved, they experienced prior constant loss of FEV1 as shown in Fig. 1. Of note, all patients received in parallel therapy with FAM (fluticasone, azithromycine, montelukast) partly in combination with beta-agonists which had already been applied > 1 month before abatacept initiation without response (Fig. 2).Fig. 2 Forced expiratory volume % before and during abatacept therapy
Infectious and other complications during abatacept
Adverse events (AE) and serious adverse events (SAE) during abatacept treatment are illustrated in Table 3. In general, abatacept administration was well tolerated; however, one patient repeatedly showed nausea, vomiting, diarrhea, fever, and fatigue for several days repeatedly upon infusion leading to termination of treatment after 7 applications. Another patient showed alopecia during treatment. Three of the patients included in the analysis developed significant infectious complications requiring hospital admission with one highly comorbid patient succumbing to urosepsis, and another patient already mentioned died due to infectious complications associated with severe peripheral artery disease unrelated to cGvHD.Table 3 Adverse and serious adverse events of abatacept treatment
Patient # AE SAE Specification
1 Yes No Fatigue, diarrhea, fever
2 No Yes Death due to gram-negative sepsis 70 days after last abatacept dose
3 No No -
4 No No -
5 No No -
6 No Yes Death due to urosepsis 24 days after last abatacept dose
7 No Yes Death due to infectious complications of peripheral artery disease
8 No No -
9 No No -
10 Yes No Alopecia after abatacept initiation
11 No No -
12 No Yes Hospital admission due to influenza A pneumonia
13 No No -
14 No No -
15 Yes No Bone pain after infusion
Discussion
cGvHD occurs with an incidence of 30–70% in patients undergoing allo-HSCT [21], and as it reduces quality of life and significantly contributes to NRM/TRM, there is still a high clinical need for effective second-line treatments [28, 29]. The underlying complex pathophysiology of cGvHD involves both B and T cell immunity and results in pleiotropic clinical manifestations resembling various autoimmune diseases [21]. Due to the involvement of auto- und alloreactive T cells in the development and course of cGvHD, there is high rationale for the use of costimulation blockade via the CTLA-4 pathway [20]. The introduction of the immunomodulatory drug abatacept has significantly improved the therapy for rheumatoid arthritis patients not responding sufficiently to conventional disease modifying antirheumatic drugs and has in this context shown efficacy and improvement of quality of life [19, 30, 31]. Based on observations in preclinical models, abatacept has been tested in combination with a CD25 monoclonal antibody in pediatric recipients of haploidentical allo-HSCT for the treatment of hyperacute GvHD, where it has shown efficacy [32]. Moreover, the safety and efficacy of abatacept for the prevention of aGvHD and treatment of SR-cGvHD were recently evaluated with promising results in phase 1 clinical trials [25, 33], and subsequent randomized phase 2 trials have been initiated (NCT0174313; NCT01954979).
In this retrospective analysis of cGvHD patients treated with abatacept at four centers, we observed a best overall response rate of 40%, which is comparable to the clinical response rate of 44% recently reported by Nahas et al. [25]. Despite the low number of patients and the retrospective character of the analysis, we observed that in particular patients with bronchiolitis obliterans syndrome (BOS) showed substantial clinical improvement after abatacept application with durable responses, stabilized lung function (Fig. 1), albeit this was not reflected by an improvement in lung grading in all patients. Given the frequently irreversible character of lung involvement due to fibrotic remodeling, we consider clinical improvement, lowering of oxygen demand, and stabilized lung function as relevant response parameters, especially in our patient cohort with mostly severe cGVHD [34]. Interestingly, it has been reported for several autoimmune diseases that costimulation blockade of the CTLA-4 axis selectively decreases the proportion of T follicular helper cells, thereby reducing T cell help for germinal center B cells [35–37]. Given that BOS is explicitly characterized by disturbance of B cell homeostasis with increased CD19+CD21- B cells and excess of B cell activation factor (BAFF) [38], abatacept might target Tfh cells in this context, which would at least partially explain the particular improvement of patients with BOS in our study. In addition, we observed a complete response in a steroid and rituximab refractory AIHA patient as previously described [39]. Despite not meeting NIH diagnostic criteria for cGvHD, we included this patient in our analysis since it has recently been reported that based on biomarker profiles, patients with signs of immune mediated damage not diagnostic for cGvHD do not significantly differ from those showing diagnostic signs of cGvHD suggesting that the current NIH diagnostic criteria may not involve all targets of cGvHD [40, 41]. Noteworthy, in the phase 1 clinical trial reported by Nahas et al., a reduction of corticosteroid usage of 51.3% was reported, while the authors state that this effect might have been overestimated due to the not blinded or randomized design of the study. In this regard, we did not observe consistent steroid reduction in patients responding to abatacept, yet most of our patients received a relatively low corticosteroid dose at start of abatacept. Interestingly, it has been reported in a preclinical model of chronic lung allograft dysfunction that bronchiolitis obliterans can be attenuated by CTLA-4-Ig administration presumably by promoting LAG3+Treg mediated anti-inflammatory effects providing a potential mechanistic explanation for the observed clinical response [42]. Of note, progression of cGvHD within three months was indicative for treatment failure, and all patients, who achieved at least a PR, were responding in the first three months. Thus, based on our experience, we would suggest discontinuing abatacept treatment, if patients do not show a response within this period. Overall, abatacept seems to be a relevant treatment option for patients with cGvHD, particularly for patients with BOS, but this has to be further investigated in future clinical trials.
Funding
Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projekt-ID 324392634 - TRR221, subproject B10 (D.W.), and by the ReForM program of the University of Regensburg (T.W.).
Declarations
Conflict of interest
D. W. received honoraria from Mallinckrodt, Novartis, Takeda, MACO, and Neovii.
The authors declare that they have no conflict of interest.
Informed consent
Informed consent was obtained from all patients for being included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Matthias Fante and Daniel Wolff contributed equally to this work. | Fatal | ReactionOutcome | CC BY | 33515310 | 18,904,556 | 2021-03 |
What was the outcome of reaction 'Urosepsis'? | Abatacept as salvage therapy in chronic graft-versus-host disease-a retrospective analysis.
The immunomodulatory fusion protein abatacept has recently been investigated for the treatment of steroid-refractory chronic graft-versus-host disease (cGvHD) in a phase 1 clinical trial. We analyzed the safety and efficacy of abatacept for cGvHD therapy in a retrospective study with 15 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received abatacept for cGvHD with a median age of 49 years. Grading was performed as part of the clinical routine according to the National Institute of Health's (NIH) consensus criteria at initiation of abatacept and 1, 3, 6, 9 and 12 months thereafter. The median time of follow-up was 191 days (range 55-393 days). Best overall response rate (ORR) was 40%. In particular, patients with bronchiolitis obliterans syndrome showed significant clinical improvement and durable responses following abatacept treatment with a response rate of 89% based on improvement in lung severity score (n = 6) or stabilized lung function (n = 4) or both (n = 3). Infectious complications CTCAE °III or higher were observed in 3/15 patients. None of the patients relapsed from the underlying malignancy. Thus, abatacept appears to be a promising treatment option for cGvHD, in particular for patients with lung involvement. However, further evaluation within a phase 2 clinical trial is required.
Introduction
While allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established, potentially curative therapy for several malignant and benign hematologic diseases, chronic graft-versus-host disease (cGvHD) remains a major complication after allo-HSCT. cGvHD occurs in up to 70% of patients after allo-HSCT and significantly contributes to impaired quality of life and non-relapse mortality (NRM)/transplant-related mortality (TRM) [1–5].
Corticosteroids represent the backbone of cGVHD treatment, but contribute to an already high morbidity and mortality by causing complications such as osteoporosis, myopathy, avascular necrosis, and glaucoma [3, 6]. A substantial number of patients does not respond to corticosteroids alone and require second-line therapy with the recently FDA-approved Bruton’s tyrosine kinase inhibitor ibrutinib or extracorporeal photopheresis [5, 7–9]. Further treatment options are usually based on retrospective or phase 1/2 clinical studies and show limited efficacy in a significant proportion of patients despite harboring the risk of toxicity including infectious complications [10–14].
Abatacept is a novel, first in class immunomodulatory drug exerting its effect by costimulatory blockade and is applied for the treatment of rheumatoid arthritis and other rheumatological diseases [15–17]. It is a recombinant fusion protein comprised of the extracellular domain of the immune checkpoint protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4) fused to the Fc fragment of IgG1 [18]. By binding with high affinity to the costimulatory receptors CD80 and CD86 on antigen presenting cells (APCs), it counteracts the costimulatory signal mediated by the ligand CD28, which is required for full T cell activation [19].
The highly complex pathophysiology of cGvHD is still poorly understood. Apart from alloreactive donor T cell responses, it involves aberrant innate immune signaling, endothelial cell injury, dysfunctional central tolerance induction (due to thymic damage as a result of the conditioning regimen or alloreactive T cells), insufficient de novo development of regulatory T cells (Treg), dysregulation of B cells, and cytokine signaling eventually resulting in chronic inflammation and fibrotic remodeling [20–22].
Since cGvHD is at least in part mediated by host reactive T cells stimulated by allogeneic antigens [23], there is high rationale for abatacept as a treatment option in cGvHD, and it has been reported that CTLA-4 blockade can prevent aGvHD and cGvHD and even reverse cGvHD in murine models [24]. Recently, abatacept has received breakthrough approval by the American Food and Drug Administration (FDA) for the prevention of acute GvHD and has shown efficacy in a phase 1 clinical trial for patients with steroid-refractory cGvHD, albeit with relatively low patient numbers [25].
Therefore, we analyzed the efficacy and safety of abatacept for the treatment of advanced cGvHD in a multicentric retrospective study.
Patients and methods
Patients
In this retrospective analysis, patients treated with abatacept for cGvHD between 2018 and 2020 at the University Hospital Regensburg (Germany), University Hospital Giessen and Marburg (Germany), University Hospital and Karolinska Institutet (Stockholm, Sweden) and University Hospital La Paz (Madrid, Spain) were included into the analysis approved by the institutional ethics review board (no.19-1586-104). Documentation of cGvHD was performed as part of clinical routine using the diagnosis and response criteria according to the National Institute of Health (NIH) consensus guidelines [26]. No new immunosuppressive agent was applied within at least 4 weeks before abatacept therapy, and response assessment was discontinued upon requirement of any additional immunosuppressive treatment post abatacept therapy. Patients received abatacept intravenously at a dose of 10 mg/kg body weight (maximum 800 mg) every 2 weeks for the first three doses and then every 4 weeks.
Definition of abatacept response and adverse events
Response to abatacept was assessed at 1, 3, 6, 9, and 12 months after start of therapy. In case of treatment with an additional immunosuppressive agent, the last response assessment for abatacept was performed at onset of new therapy. Last follow-up of the present analysis was January 2020. Complete remission (CR) was defined as resolution of all organ manifestations of cGvHD. Improvement of at least one organ grade without progression of cGvHD at other organs was classified as partial response (PR); mixed response was defined as simultaneous improvement in one organ and progression in another organ. Patients who showed no change in organ grading were classified as stable disease (SD). Failure-free survival (FFS) was defined as absence of relapse or non-relapse mortality or addition of further systemic therapy. Overall response rates (ORR) were calculated based on intention to treat analysis. Infectious complications were assessed and classified according to the common terminology criteria for adverse events version 5.0 (CTCAE 5.0) with toxicities captured in the analysis starting from grade III.
Results
Patient characteristics
We treated 15 patients with abatacept for cGvHD at our centers between 2018 and 2020. Among those patients, the diagnoses leading to allo-HSCT were myeloid disorders (acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasia (MPN)) in 10 patients, lymphatic malignancies (acute lymphoblastic leukemia (ALL), and Hodgkin lymphoma (HL)) in four patients and one patient suffering from CTLA-4 haploinsufficiency.
All patients had received peripheral blood stem cells (PBSC) as graft source with 11 patients grafted from an HLA-matched sibling (5 patients) or an unrelated donor (8 patients). HLA-matched donors were defined as 10/10 match. One patient had received an HLA-C mismatched graft from an unrelated donor, and one patient received a haploidentical graft from a related donor. Acute GvHD grade II or higher according to Glucksberg criteria occurred in 11 patients (85%). cGvHD onset was quiescent in 8 patients, de novo in three patients and progressive in four patients. Most of the patients (n = 12; 80%), who received abatacept, had severe cGvHD. One patient included in the analysis had mild cGvHD (prior history of moderate cGvHD) and received abatacept due to intolerance to other immunosuppressive agents. One patient was treated for autoimmune-hemolytic anemia (AIHA) refractory to corticosteroids and rituximab not fulfilling the NIH criteria for cGvHD falling in the category “undefined other cGvHD” [26, 27]. The majority of the patients had steroid dependent cGvHD (n = 10, 67%, all others steroid-refractory cGvHD (n = 5; 33%)). A platelet count < 100/nl was observed in 4 patients (27%) at the time of abatacept initiation.
The most common organ manifestations of cGvHD were skin (n = 11; 73%), lung (n = 11; 73%), eyes (n = 10; 67%), and oral cavity (n = 10; 67%). Abatacept was initiated on median day 1848 (range 432–7953) after allo-HSCT and on day 1592 (range 28–7864) after cGvHD onset, respectively. The corticosteroid dose at abatacept initiation was 0.34 mg/kg in median (range 0,12–2 mg/kg). The patients included in the analysis had received a median of 4.6 prior treatment lines (range 2–5) for cGvHD. Within 3 months before abatacept treatment was started, most patients did not undergo new immunosuppressive treatments (80%). The remaining patients (20%), who underwent new immunosuppressive treatments within 3 months, were progressive or refractory to the initiated treatment.
Median follow-up after treatment was 179 days (range 55–393). Patient characteristics including age, gender, diagnosis, donor type, stem cell source, conditioning regimen, GvHD prophylaxis, history of acute GvHD, and chronic GvHD are shown in Table 1.Table 1 Patient characteristics
Patient characteristics Value
Patients 15
Female, n (%) 10
Male, n (%) 5
Age, median (range)* 49 (5–70)
Diagnosis
AML, n (%) 7 (47)
ALL, n (%) 2 (13)
MPN (%) 3 (15)
Others, n (%) 3 (15)
Donor type
HLA-matched unrelated, n (%) 7 (47)
HLA-mismatched unrelated, n (%) 1 (7)
HLA-matched related, n (%) 6 (40)
HLA-mismatched related, n (%) 0
Haploidentical related, n (%) 1 (7)
Sex mismatch: female to male
Yes, n (%) 1 (7)
No, n (%) 14 (93)
Stem cell source
Peripheral blood stem cells, n (%) 14 (93)
Bone marrow, n (%) 1 (7)
GvHD prophylaxis
ATG/CsA/MTX, n (%) 3 (20)
CsA/MTX, n (%) 5 (33)
CsA/MMF, n (%) 1 (7)
Other 6 (40)
History of aGvHD
Grades 0–I, n (%) 4 (27)
Grades II–IV, n (%) 11 (73)
Characteristics Value
Onset of cGvHD after allo-SCT, median days (range) 256 (76–597)
Time point of abatacept treatment after allo-SCT, median days, (range) 1848 (432–7953)
Time point of abatacept treatment after cGvHD onset, median days, (range) 1592 (133–7864)
Age at abatacept initiation, median (range) 49 (5–70)
Number of abatacept doses, median (range) 7.1 (1–20)
cGvHD, n (%)
Mild 1 (7)
Moderate 0
Severe
non-NIH defined (AIHA)
13 (87)
1 (7)
Steroid response of cGvHD
Steroid resistance 5 (33)
Steroid dependence 10 (67)
Number of organ involvement of cGvHD, n (%)
One 1 (7)
Two 1 (7)
Three 5 (33)
Four or more 8 (53)
Type of cGvHD organ involvement, n (%)
Skin 11 (73)
Oral 10 (67)
Eyes 10 (67)
Liver 2 (13)
Gut 4 (27)
Lung 11 (73)
Musculoskeletal 7 (47)
Genital 2 (13)
AIHA 1 (7)
ISM at the beginning of abatacept, n (%)
No ISM 0
One ISM 5 (33)
Two ISM 8 (53)
Three or more ISM 2 (13)
Number of prior therapies before abatacept, n (%)
One 2 (13)
Two 2 13)
Three 1 (7)
Four or more prior therapies 10 (67)
New ISM within 3 months before abatacept, n (%)
Yes 3 (20)
No 12 (80)
n number of patients, AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, MPN myeloproliferative neoplasia, HLA human leukocyte antigen, ATG anti-thymocyte globulin, CsA ciclosporin A, MTX methotrexate, MMF mycophenolate mofetil, GvHD graft-versus-host disease, aGvHD acute GvHD, cGvHD chronic GvHD, ISM immunosuppressive medication
Response to abatacept
Response to abatacept treatment is illustrated in Fig. 1 and Table 2 at the different time points of this analysis.Fig. 1 Clinical course during abatacept treatment
Table 2 Duration of abatacept treatment and clinical course
Patient # Day of start IS at start # of doses Organ involvement (grade) at start Skin features at start 1 m RR 2 m RR 3 m RR 6 m RR 9 m RR 12 m RR Follow up
1 7953 GC, E, MMF 7 s (0), e (3), m (0), f (0), lu (3) - SD SD SD SD - - Stabilized lung function, abatacept discontinued due to prolonged fatigue and diarrhea after administration
2 1596 GC, Rux 6 s (3), e (1), m (1), f (2), lu (2) S PR PR PR - - - Improvement of lung GvHD, new IS with ibrutinib and tocilizumab after 6 months
3 3261 GC, CsA 2 s (3), e (0), m (2), f (2), lu (0) S SD SD SD SD - - New IS with daratumumab after no improvement of oral ulcers
4 1425 GC 4 s (3), e (1), m (1), f (2), lu (2) S SD MR SD - - - Death due to aortic valve rupture (preexisting aortic valve insufficiency)
5 949 GC, Rux 3 s (3), e (2), m (0), f (2), lu (0) S SD SD - - - - New IS with Treg after 2 months
6 722 GC 10 s (0), e (3), m (0), f (0), lu (3) - PR PR PR PR - - Stabilized lung GvHD and improved functional capacity, death due to sepsis 9 months after abatacept start
7 1318 GC 1 s (0), e (0), m (1), f (0), lu (0) - PR PR - - - - Abatacept was given due to intolerance to IS agents and multiple infectious complications; death due to infectious complications of PAD
8 4587 GC, Bari 5 s (3), e (0), m (0), f (2), lu (0) S SD SD SD - - - New IS with tofacitinib after persisting arthralgia
9* 1311 GC, Ima 14 s (1), e (1), m (1), gi (1), f (0), lu (3) L PR PR PR PR PR PR Durable improvement of lung and skin GvHD. Less oxygen demand, reduced coughing
10* 432 GC, E 14 s (3), e (1), m (1), f (0), lu (0) S SD SD PR PR PR PR Improvement of ocular GvHD
11 1162 GC, Tac 9 s (1), e (3), m (1), f (0), lu (3) L MR MR MR MR - - Stabilized lung function, progressive oral affection, new IS with ruxolitinib after 9 months
12* 517 Toc 13 s (2), m (1), gi (1), li (1), f (0), lu (3) L PR PR PR PR PR PR Complete resolution of s, m, gi and li GvHD. Significant improvement of lung GvHD (reduction from grades 3 to 1)
13* 157 GC 4 AIHA - CR CR CR CR NR NR Complete resolution of AIHA
14* 469 GC, Ibru s (0), e (0), m (1), gi (0), f (0), lu (1) - SD SD SD NR NR NR Stabilized lung function
15* 1864 CsA 10 s (1), e (1), m (2), gi (0), f (2), lu (3) L SD PR PR PR PR NR Increased mobility and improved lung symptoms
Median 1848 7
1/3/6/9/12-month RR 1/3/6/12-month response rate, respectively; GC glucocorticoid; E everolimus; MMF mycophenolate mofetil; Rux ruxolitinib; CsA cyclosporine A; Bari baricitinib; Ima imatinib; Tac tacrolimus; Toc tocilizumab; Ibru ibrutinib; s skin; e eyes; m mouth; f fascia; lu lungs; ge genital; S sclerotic features; L lichen planus-like features; PD progressive disease; SD stable disease; PR partial response; MR mixed response; NR not reached; Treg regulatory T cells; IS immunosuppression; PAD peripheral artery disease; QOL quality of life; AIHA autoimmune hemolytic anemia; *ongoing therapy
Response to abatacept at 1 month
One month after first administration of abatacept, the patient (7%) with AIHA showed CR, 5 (33%) patients had PR, one patient (7%) showed MR with improved lung function but progressive oral affection, and 8 patients (53%) presented with SD. None of the patients required start of an additional immunosuppressive therapy. The overall response rate (ORR) at 1 month was 40%, and failure-free survival (FFS) was 100%.
Response to abatacept at 3 months
At 3 months after start of abatacept therapy, one patient showed CR (7%), 5 (33%) patients had PR, one patient showed MR (7%), and 6 patients (40%) had SD. One patient who had SD started a new immunosuppression and another patient with a PR succumbed to infectious complications of severe peripheral artery disease unrelated to abatacept. ORR at 3 months was therefore 40% with an FFS of 87%.
Response to abatacept at 6 and 9 months
The 6 months follow-up was reached by nine patients with one patient remaining in CR (7%), four patients achieving PR (27%), one MR (7%) with sustained stabilized lung function but impaired oral affection, and two patients with SD (13%). At termination of our analysis, one patient was still treated with abatacept but has not reached the 6 months follow-up yet. One patient with PR started a new IS with ibrutinib and tocilizumab, and another patient who was in SD discontinued abatacept and was switched to tofacitinib due to persisting arthralgia. One highly comorbid patient with preexisting aortic valve insufficiency died due to aortic valve rupture. Thus, the ORR at 6 months was 33% with an FFS of 64%.
Nine months after initiation of abatacept treatment, four patients still received therapy and two patients currently still receiving abatacept have not reached the time point yet. Of the remaining patients, three showed a PR (20%), one patient discontinued abatacept due to sustained and not improved oral ulcers, and another patient died due to urosepsis, displaying an ORR of 23% with an FFS of 31%.
Response to abatacept at 12 months
At 12 months, three patients were still treated with abatacept, and three who currently receive abatacept therapy have not reached the time point yet. Three patients still had PR (25%) resulting in an ORR of 25% with FFS of 25%.
Response in patients with lung involvement of cGvHD
Interestingly, we observed that patients with lung involvement (n = 9) particularly benefitted from therapy with abatacept with an overall response rate of 89% based on improvement in lung severity score (n = 6), lung function as measured by FEV1 in Fig. 1 (n = 4) or both (n = 3). Of note, although only a stabilization on abatacept was achieved, they experienced prior constant loss of FEV1 as shown in Fig. 1. Of note, all patients received in parallel therapy with FAM (fluticasone, azithromycine, montelukast) partly in combination with beta-agonists which had already been applied > 1 month before abatacept initiation without response (Fig. 2).Fig. 2 Forced expiratory volume % before and during abatacept therapy
Infectious and other complications during abatacept
Adverse events (AE) and serious adverse events (SAE) during abatacept treatment are illustrated in Table 3. In general, abatacept administration was well tolerated; however, one patient repeatedly showed nausea, vomiting, diarrhea, fever, and fatigue for several days repeatedly upon infusion leading to termination of treatment after 7 applications. Another patient showed alopecia during treatment. Three of the patients included in the analysis developed significant infectious complications requiring hospital admission with one highly comorbid patient succumbing to urosepsis, and another patient already mentioned died due to infectious complications associated with severe peripheral artery disease unrelated to cGvHD.Table 3 Adverse and serious adverse events of abatacept treatment
Patient # AE SAE Specification
1 Yes No Fatigue, diarrhea, fever
2 No Yes Death due to gram-negative sepsis 70 days after last abatacept dose
3 No No -
4 No No -
5 No No -
6 No Yes Death due to urosepsis 24 days after last abatacept dose
7 No Yes Death due to infectious complications of peripheral artery disease
8 No No -
9 No No -
10 Yes No Alopecia after abatacept initiation
11 No No -
12 No Yes Hospital admission due to influenza A pneumonia
13 No No -
14 No No -
15 Yes No Bone pain after infusion
Discussion
cGvHD occurs with an incidence of 30–70% in patients undergoing allo-HSCT [21], and as it reduces quality of life and significantly contributes to NRM/TRM, there is still a high clinical need for effective second-line treatments [28, 29]. The underlying complex pathophysiology of cGvHD involves both B and T cell immunity and results in pleiotropic clinical manifestations resembling various autoimmune diseases [21]. Due to the involvement of auto- und alloreactive T cells in the development and course of cGvHD, there is high rationale for the use of costimulation blockade via the CTLA-4 pathway [20]. The introduction of the immunomodulatory drug abatacept has significantly improved the therapy for rheumatoid arthritis patients not responding sufficiently to conventional disease modifying antirheumatic drugs and has in this context shown efficacy and improvement of quality of life [19, 30, 31]. Based on observations in preclinical models, abatacept has been tested in combination with a CD25 monoclonal antibody in pediatric recipients of haploidentical allo-HSCT for the treatment of hyperacute GvHD, where it has shown efficacy [32]. Moreover, the safety and efficacy of abatacept for the prevention of aGvHD and treatment of SR-cGvHD were recently evaluated with promising results in phase 1 clinical trials [25, 33], and subsequent randomized phase 2 trials have been initiated (NCT0174313; NCT01954979).
In this retrospective analysis of cGvHD patients treated with abatacept at four centers, we observed a best overall response rate of 40%, which is comparable to the clinical response rate of 44% recently reported by Nahas et al. [25]. Despite the low number of patients and the retrospective character of the analysis, we observed that in particular patients with bronchiolitis obliterans syndrome (BOS) showed substantial clinical improvement after abatacept application with durable responses, stabilized lung function (Fig. 1), albeit this was not reflected by an improvement in lung grading in all patients. Given the frequently irreversible character of lung involvement due to fibrotic remodeling, we consider clinical improvement, lowering of oxygen demand, and stabilized lung function as relevant response parameters, especially in our patient cohort with mostly severe cGVHD [34]. Interestingly, it has been reported for several autoimmune diseases that costimulation blockade of the CTLA-4 axis selectively decreases the proportion of T follicular helper cells, thereby reducing T cell help for germinal center B cells [35–37]. Given that BOS is explicitly characterized by disturbance of B cell homeostasis with increased CD19+CD21- B cells and excess of B cell activation factor (BAFF) [38], abatacept might target Tfh cells in this context, which would at least partially explain the particular improvement of patients with BOS in our study. In addition, we observed a complete response in a steroid and rituximab refractory AIHA patient as previously described [39]. Despite not meeting NIH diagnostic criteria for cGvHD, we included this patient in our analysis since it has recently been reported that based on biomarker profiles, patients with signs of immune mediated damage not diagnostic for cGvHD do not significantly differ from those showing diagnostic signs of cGvHD suggesting that the current NIH diagnostic criteria may not involve all targets of cGvHD [40, 41]. Noteworthy, in the phase 1 clinical trial reported by Nahas et al., a reduction of corticosteroid usage of 51.3% was reported, while the authors state that this effect might have been overestimated due to the not blinded or randomized design of the study. In this regard, we did not observe consistent steroid reduction in patients responding to abatacept, yet most of our patients received a relatively low corticosteroid dose at start of abatacept. Interestingly, it has been reported in a preclinical model of chronic lung allograft dysfunction that bronchiolitis obliterans can be attenuated by CTLA-4-Ig administration presumably by promoting LAG3+Treg mediated anti-inflammatory effects providing a potential mechanistic explanation for the observed clinical response [42]. Of note, progression of cGvHD within three months was indicative for treatment failure, and all patients, who achieved at least a PR, were responding in the first three months. Thus, based on our experience, we would suggest discontinuing abatacept treatment, if patients do not show a response within this period. Overall, abatacept seems to be a relevant treatment option for patients with cGvHD, particularly for patients with BOS, but this has to be further investigated in future clinical trials.
Funding
Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projekt-ID 324392634 - TRR221, subproject B10 (D.W.), and by the ReForM program of the University of Regensburg (T.W.).
Declarations
Conflict of interest
D. W. received honoraria from Mallinckrodt, Novartis, Takeda, MACO, and Neovii.
The authors declare that they have no conflict of interest.
Informed consent
Informed consent was obtained from all patients for being included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Matthias Fante and Daniel Wolff contributed equally to this work. | Fatal | ReactionOutcome | CC BY | 33515310 | 18,904,612 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaemia'. | Early stent thrombosis confirmed in a cancer patient receiving regorafenib, despite triple antithrombotic therapy: a case report.
While developments in oncology have lengthened survival in patients with cancer, such patients often develop cardiovascular diseases. Thus, percutaneous coronary intervention (PCI) is frequently undertaken in them. Although stent thrombosis remains a fatal complication in stent-based PCI, worldwide consensus panels tend to recommend shorter duration of dual-antiplatelet therapy. This is based on its clinical efficacy that has resulted from technological innovation. However, there is insufficient discussion on the risk of stent thrombosis in cancer patients with coronary artery disease, especially in those undergoing chemotherapeutic regimens that have a risk for thrombosis, such as regimens with the anti-vascular endothelial growth factor. Presented here is a case of early stent thrombosis that occurred in a cancer patient on regorafenib, despite the administration of triple antithrombotic therapy. Case presentation A 66-year-old Japanese male patient received regorafenib for metastatic colorectal carcinoma and apixaban for deep vein thrombosis. Coronary angiography revealed severe stenosis in the proximal left anterior descending artery. A sirolimus-eluting stent was implanted, without malapposition and under-expansion, under intravascular ultrasound guidance while administering a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day). However, he was admitted to the hospital for exacerbation of heart failure 1 month after PCI. Coronary angiography revealed contrastive defects in the previous stent. Optical frequency domain imaging confirmed stent thrombosis. PCI was successfully performed with perfusion balloon long-inflation. Antithrombotic therapy was enhanced (aspirin: 100 mg/day, ticagrelor: 120 mg/day, and apixaban: 10 mg/day) and regorafenib was discontinued permanently. While ischemic events did not occur thereafter, the patient died due to metastatic carcinoma progression.
This case suggests that anti-vascular endothelial growth factor might contribute to early stent thrombosis, despite triple antithrombotic therapy. Further discussion is needed on the surveillance and management of cancer patients with coronary artery disease receiving chemotherapy, which carries a risk of thrombosis.
Background
Cardio-oncology is a rapidly growing subspeciality worldwide. Recent oncological developments have led to favorable clinical outcomes in cancer patients; however, many cancer survivors develop cardiovascular diseases. As a result, percutaneous coronary intervention (PCI) is frequently performed in cancer patients, who also develop coronary artery disease (CAD) while receiving chemotherapy.
Stent thrombosis (ST) is a rare but serious complication of PCI. Malignant disease is known as a strong risk factor for the development of ST and hemorrhage after stent implantation [1]. In addition, many modern chemotherapies are associated with vascular complications such as thrombosis and major bleeding [2]. Cancer and its treatment with chemotherapy are associated with a potential risk of thrombotic and bleeding complications in patients undergoing PCI. However, currently, there is insufficient evidence for optimal prevention and risk stratification of ST in these patients.
Described below is a case of early ST that was confirmed by optical frequency domain imaging (OFDI). In this case, ST occurred in a cancer patient receiving anti-vascular endothelial growth factor (VEGF) therapy in our hospital despite the administration of a triple antithrombotic therapy.
Case presentation
A 66-year-old Japanese male patient had received regorafenib (160 mg/day) as an anticancer treatment for metastatic colorectal carcinoma. His medical history included hypertension, diabetes mellitus, dyslipidemia, chronic heart failure, deep vein thrombosis (DVT), and permanent pacemaker implantation due to complete atrioventricular block. His DVT had been managed with low-dose apixaban (5 mg/day; body weight: 75 kg, creatinine: 1.0 mg/dL) to avoid bleeding complications.
Two months ago, he had suffered from non-ST-elevation myocardial infarction with the high-lateral (HL) branch as the culprit lesion, accompanied by chest discomfort; the HL branch occlusion was treated with balloon dilation only to avoid the need of a long-term triple antithrombotic therapy. At the same time, coronary angiography (CAG) revealed severe stenosis in the proximal left anterior descending (LAD) artery. A fractional flow reserve value of 0.72 confirmed a physiologically significant lesion. After PCI for the HL branch, regorafenib was withdrawn temporarily, and a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day) was successfully continued for two months without bleeding complications. Subsequently, the patient underwent PCI for severe stenosis in the LAD lesion two months after PCI for HL, as he demonstrated good tolerance to the triple antithrombotic therapy. Other medications administered included bisoprolol (1.25 mg/day), enalapril (2.5 mg/day), furosemide (20 mg/day), esomeprazole (20 mg/day), amlodipine (5 mg/day), sitagliptin (50 mg/day), mitiglinide (30 mg/day), and insulin degludec (9 units). In addition, routine blood testing revealed an elevated level of B-type natriuretic peptide (BNP), normal kidney function, high value of HbA1c, and mild anemia (BNP: 191.6 pg/mL, creatinine: 0.68 mg/dL, estimated glomerular filtration rate: 89.3 mL/minute/1.73 m2, HbA1c: 8.4%, hemoglobin: 9.9 g/dL, and platelet count: 318 × 103/µL). He was classified as having a high thrombotic and bleeding risk at this time, according to the CREDO-Kyoto thrombotic and bleeding risk scores. A sirolimus-eluting stent, which is a drug-eluting stent (DES) (Ultimaster Tansei 3.5/38 mm; Terumo Corporation, Tokyo, Japan), was implanted in the LAD lesion without malapposition or significant under-expansion, as confirmed by intravascular ultrasound imaging (IVUS) analysis (Fig. 1). After PCI for the LAD, regorafenib was resumed because it exhibited a clinical effect on the patient's cancer. Nevertheless, the patient was admitted to our hospital for congestive heart failure with dyspnea one month later (BNP: 1,512.5 pg/mL). Echocardiography demonstrated new severe hypokinesis of the anteroseptal wall and apex. Despite continued triple antithrombotic therapy, CAG revealed focal and eccentric contrastive defects in the previous LAD stent, and OFDI confirmed ST (Fig. 2a–e). A 3.5/20 mm perfusion balloon (Ryusei, Kaneka Medical, Tokyo, Japan) was inflated for 3 min using an embolic protection device (Fig. 2f). CAG and OFDI confirmed optimal initial gain in the ST site and thrombolysis in myocardial infarction flow grade 3, with no complications including distal emboli (Fig. 2g–k). Antithrombotic therapy was further enhanced temporarily to prevent the recurrence of ST; it included aspirin (100 mg/day), ticagrelor (120 mg/day), and apixaban (10 mg/day). The administration of regorafenib was discontinued after PCI for ST in the LAD, and aspirin and ticagrelor were discontinued 1 and 2 months later, respectively. No further thromboembolic events (including definite/probable ST) were observed, and heart failure was managed well. However, he died due to the progression of metastatic colorectal carcinoma about 3 months after ST onset.Fig. 1 Percutaneous coronary intervention for left anterior descending artery under intravascular ultrasound guidance. a, b Severe stenosis in the left anterior descending (LAD) artery (arrowhead) on initial coronary angiography (CAG). c Stent implantation in the LAD. d–g Final CAG showing an optimal result, with longitudinal and cross-sectional views in intravascular ultrasound imaging; acceptable stent expansion is confirmed
Fig. 2 Early stent thrombosis and revascularization. a Focal and eccentric contrastive defect in the previous left anterior descending stent. b–e Cross-sectional and longitudinal views of the stent thrombosis in optical frequency domain imaging (OFDI). f 3.5-mm perfusion balloon is dilated for 3 min. g Final coronary angiography reveals reduction of the contrastive defect and thrombolysis in myocardial infarction flow grade 3 without distal emboli. h–k Cross-sectional and longitudinal views in OFDI showing an increase in the lumen area and a small amount of residual thrombus
Discussion and conclusions
In this modern stent-based PCI era, ST represents a fatal and life-threatening complication. According to previous reports, the risk of ST is strongly associated with both, the patient background and procedural aspects [1, 3]. Certain patient background factors are independent predictors of a bleeding risk; malignant disease is a strong risk factor for major bleeding after PCI, as well as ST [1]. Our patient was classified as having a high thrombotic (4 points: anemia, heart failure, diabetes mellitus) and bleeding (4 points: heart failure, prior myocardial infarction, malignancy) risk, according to the CREDO-Kyoto thrombotic and bleeding risk scores [3]. Thus, we always had to consider the tradeoffs between the thrombotic and bleeding risks and PCI while caring for him.
The most frequent optical coherence tomography findings in early ST (within 30 days after index PCI) are uncovered struts and under-expansion [4]. Incomplete neointimal coverage of the struts in the early phase is normal, but the risk of ST associated with this procedure needs to be minimized. This risk could be reduced by optimizing stent placement with intracoronary imaging techniques and developing newer DES technology [1]. Moreover, dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor blocker after coronary stent implantation has been effective in preventing ST, and has been the standard treatment. Regarding P2Y12 receptor blockers, prasugrel or ticagrelor, in combination with aspirin, has been associated with a greater reduction in ST as compared to a combination of clopidogrel and aspirin [5, 6]. Furthermore, among stented patients with acute coronary syndrome treated by DAPT, low-dose rivaroxaban administration has been associated with a reduction in ST [7]. Thus, antithrombotic therapy after PCI has been established worldwide, but the optimal duration of DAPT remains controversial. Recent global guidelines recommend a shorter duration of DAPT for clinical efficacy. Additionally, it is recommended that the duration of the combination of triple antithrombotic therapy with DAPT and oral anticoagulants be as brief as possible [8]. However, there remains a lack of discussion regarding an appropriate antiplatelet therapy after PCI for cancer patients who are or are not undergoing chemotherapy. In our patient, although new-generation DES implantation was optimized by IVUS and a more potent antithrombotic therapy (DAPT and direct oral anticoagulant [DOAC]) was continued, early ST still occurred. This suggests that a standardized antithrombotic drug reduction may cause life-threatening ST in cancer patients receiving chemotherapy. The patient in our case was managed by changing the P2Y12 receptor blocker, increasing the DOAC dose, and withdrawing regorafenib until an adequate neointimal coverage of the struts was achieved. Thus, the risk of ST and the optimal duration of DAPT in cancer patients undergoing chemotherapy should be explored further.
While the association between venous thromboembolism (VTE) and malignancy is well-discussed, arterial thrombosis has more recently been recognized as a serious complication of cancer and chemotherapy. One study, based on a large database in the USA, reported that the incidence of arterial thromboembolic events (ATEs) in patients with cancer at 6 months was 4.7% [9]; patients with lung, gastric, or pancreatic cancers had the highest rates of ATEs (8.3, 6.5, and 5.9%, respectively). Moreover, an advanced stage of cancer was associated with a significant increase in the incidence of ATEs (stage 0 vs. stage 4: 2.3% vs. 7.7% at 6 months). Furthermore, certain chemotherapeutic agents, including VEGF inhibitors, have been reported to be associated with ATEs [10]; cisplatin, nilotinib, ponatinib, 5-FU, and capecitabine are particularly associated with a high incidence of coronary artery thrombotic events. Thus, while determining the risk of ischemic events after PCI, physicians should take into account the type of cancer, progression, and chemotherapeutic regimen. Similarly, the risks of occurrence and recurrence of cancer-associated VTE were found to vary according to the type and spread of the malignant disease [11]. Recent clinical trials assessing DOACs for cancer-associated VTE reported that DOACs seemed to be a reasonable treatment for VTE in such patients [12]. However, it should be noted that in these trials, bleeding events occurred in cases with gastrointestinal and urological tumors; such an occurrence of bleeding events in different types of cancers may also apply to DAPT after PCI in cancer patients. The traditional stratification of risks for bleeding and ischemic events after coronary stent implantation may need to be supplemented with information on the cancer type, progression, and chemotherapeutic regimen.
Regorafenib, an oral multi-targeted receptor tyrosine kinase inhibitor that targets VEGF (thereby affecting cell proliferation and angiogenesis), has been indicated for metastatic colorectal carcinoma. However, it is associated with cardiovascular complications such as hypertension, hemorrhage, thrombosis, and heart failure [2, 10, 13]. Regorafenib was previously reported to be less involved in thrombosis as compared to similar drugs, and has been relatively well-tolerated by patients [13]. However, increased platelet activation, endothelial dysfunction, and dysfunctional nitric oxide metabolism due to VEGF inhibitors result in thrombosis, because VEGF is an important signaling factor for endothelial cell health, which is essential for blood vessel formation and maintenance [10]. Thus, VEGF is important for endothelial cell health and vascular repair in patients undergoing PCI. As a result, VEGF inhibitors, such as regorafenib, might be associated with ST. In our case, it was important to consider a change in the chemotherapeutic regimen before PCI. However, the patient wished to continue regorafenib, because it was an almost final-line treatment for his cancer. Oncology and cardiovascular experts should make every effort to provide optimal medical care while respecting the patients' wishes.
The management of hemodynamically significant CAD in cancer patients, especially those undergoing chemotherapy, has not been fully established. Optimal stent replacement during PCI under intracoronary imaging could reduce the risk of ST, but this may be insufficient. The optimal treatment strategy for cancer patients with CAD, including invasive revascularization, antithrombotic therapy, and chemotherapy, needs to be verified. Future developments in the field of cardio-oncology will need to adapt to changes in the patient population and focus on optimal prevention and surveillance strategies accordingly.
Abbreviations
ATEsarterial thromboembolic events
BNPB-type natriuretic peptide
CADcoronary artery disease
CAGcoronary angiography
DAPTdual-antiplatelet therapy
DESdrug-eluting stent
DOACdirect oral anticoagulant
DVTdeep venous thrombosis
HLhigh-lateral
OFDIoptical frequency domain imaging
IVUSintravascular ultrasound imaging
LADleft anterior descending
PCIpercutaneous coronary intervention
STstent thrombosis
VEGFvascular endothelial growth factor
VTEvenous thromboembolism
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KS and TO managed the patient and wrote and revised the manuscript. KY, KZ and SM revised the manuscript and figures. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and in its additional files.
Ethics approval and consent to participate
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or with comparable ethical standards.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images and videos. A copy of the written consent is available for review by the editor of this journal.
Competing interests
The authors declare that they have no competing interests. | AMLODIPINE BESYLATE, APIXABAN, ASPIRIN, BISOPROLOL, ENALAPRIL, ESOMEPRAZOLE MAGNESIUM, FUROSEMIDE, INSULIN DEGLUDEC, MITIGLINIDE, PRASUGREL HYDROCHLORIDE, REGORAFENIB, SITAGLIPTIN | DrugsGivenReaction | CC BY | 33516171 | 18,873,767 | 2021-01-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure'. | Early stent thrombosis confirmed in a cancer patient receiving regorafenib, despite triple antithrombotic therapy: a case report.
While developments in oncology have lengthened survival in patients with cancer, such patients often develop cardiovascular diseases. Thus, percutaneous coronary intervention (PCI) is frequently undertaken in them. Although stent thrombosis remains a fatal complication in stent-based PCI, worldwide consensus panels tend to recommend shorter duration of dual-antiplatelet therapy. This is based on its clinical efficacy that has resulted from technological innovation. However, there is insufficient discussion on the risk of stent thrombosis in cancer patients with coronary artery disease, especially in those undergoing chemotherapeutic regimens that have a risk for thrombosis, such as regimens with the anti-vascular endothelial growth factor. Presented here is a case of early stent thrombosis that occurred in a cancer patient on regorafenib, despite the administration of triple antithrombotic therapy. Case presentation A 66-year-old Japanese male patient received regorafenib for metastatic colorectal carcinoma and apixaban for deep vein thrombosis. Coronary angiography revealed severe stenosis in the proximal left anterior descending artery. A sirolimus-eluting stent was implanted, without malapposition and under-expansion, under intravascular ultrasound guidance while administering a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day). However, he was admitted to the hospital for exacerbation of heart failure 1 month after PCI. Coronary angiography revealed contrastive defects in the previous stent. Optical frequency domain imaging confirmed stent thrombosis. PCI was successfully performed with perfusion balloon long-inflation. Antithrombotic therapy was enhanced (aspirin: 100 mg/day, ticagrelor: 120 mg/day, and apixaban: 10 mg/day) and regorafenib was discontinued permanently. While ischemic events did not occur thereafter, the patient died due to metastatic carcinoma progression.
This case suggests that anti-vascular endothelial growth factor might contribute to early stent thrombosis, despite triple antithrombotic therapy. Further discussion is needed on the surveillance and management of cancer patients with coronary artery disease receiving chemotherapy, which carries a risk of thrombosis.
Background
Cardio-oncology is a rapidly growing subspeciality worldwide. Recent oncological developments have led to favorable clinical outcomes in cancer patients; however, many cancer survivors develop cardiovascular diseases. As a result, percutaneous coronary intervention (PCI) is frequently performed in cancer patients, who also develop coronary artery disease (CAD) while receiving chemotherapy.
Stent thrombosis (ST) is a rare but serious complication of PCI. Malignant disease is known as a strong risk factor for the development of ST and hemorrhage after stent implantation [1]. In addition, many modern chemotherapies are associated with vascular complications such as thrombosis and major bleeding [2]. Cancer and its treatment with chemotherapy are associated with a potential risk of thrombotic and bleeding complications in patients undergoing PCI. However, currently, there is insufficient evidence for optimal prevention and risk stratification of ST in these patients.
Described below is a case of early ST that was confirmed by optical frequency domain imaging (OFDI). In this case, ST occurred in a cancer patient receiving anti-vascular endothelial growth factor (VEGF) therapy in our hospital despite the administration of a triple antithrombotic therapy.
Case presentation
A 66-year-old Japanese male patient had received regorafenib (160 mg/day) as an anticancer treatment for metastatic colorectal carcinoma. His medical history included hypertension, diabetes mellitus, dyslipidemia, chronic heart failure, deep vein thrombosis (DVT), and permanent pacemaker implantation due to complete atrioventricular block. His DVT had been managed with low-dose apixaban (5 mg/day; body weight: 75 kg, creatinine: 1.0 mg/dL) to avoid bleeding complications.
Two months ago, he had suffered from non-ST-elevation myocardial infarction with the high-lateral (HL) branch as the culprit lesion, accompanied by chest discomfort; the HL branch occlusion was treated with balloon dilation only to avoid the need of a long-term triple antithrombotic therapy. At the same time, coronary angiography (CAG) revealed severe stenosis in the proximal left anterior descending (LAD) artery. A fractional flow reserve value of 0.72 confirmed a physiologically significant lesion. After PCI for the HL branch, regorafenib was withdrawn temporarily, and a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day) was successfully continued for two months without bleeding complications. Subsequently, the patient underwent PCI for severe stenosis in the LAD lesion two months after PCI for HL, as he demonstrated good tolerance to the triple antithrombotic therapy. Other medications administered included bisoprolol (1.25 mg/day), enalapril (2.5 mg/day), furosemide (20 mg/day), esomeprazole (20 mg/day), amlodipine (5 mg/day), sitagliptin (50 mg/day), mitiglinide (30 mg/day), and insulin degludec (9 units). In addition, routine blood testing revealed an elevated level of B-type natriuretic peptide (BNP), normal kidney function, high value of HbA1c, and mild anemia (BNP: 191.6 pg/mL, creatinine: 0.68 mg/dL, estimated glomerular filtration rate: 89.3 mL/minute/1.73 m2, HbA1c: 8.4%, hemoglobin: 9.9 g/dL, and platelet count: 318 × 103/µL). He was classified as having a high thrombotic and bleeding risk at this time, according to the CREDO-Kyoto thrombotic and bleeding risk scores. A sirolimus-eluting stent, which is a drug-eluting stent (DES) (Ultimaster Tansei 3.5/38 mm; Terumo Corporation, Tokyo, Japan), was implanted in the LAD lesion without malapposition or significant under-expansion, as confirmed by intravascular ultrasound imaging (IVUS) analysis (Fig. 1). After PCI for the LAD, regorafenib was resumed because it exhibited a clinical effect on the patient's cancer. Nevertheless, the patient was admitted to our hospital for congestive heart failure with dyspnea one month later (BNP: 1,512.5 pg/mL). Echocardiography demonstrated new severe hypokinesis of the anteroseptal wall and apex. Despite continued triple antithrombotic therapy, CAG revealed focal and eccentric contrastive defects in the previous LAD stent, and OFDI confirmed ST (Fig. 2a–e). A 3.5/20 mm perfusion balloon (Ryusei, Kaneka Medical, Tokyo, Japan) was inflated for 3 min using an embolic protection device (Fig. 2f). CAG and OFDI confirmed optimal initial gain in the ST site and thrombolysis in myocardial infarction flow grade 3, with no complications including distal emboli (Fig. 2g–k). Antithrombotic therapy was further enhanced temporarily to prevent the recurrence of ST; it included aspirin (100 mg/day), ticagrelor (120 mg/day), and apixaban (10 mg/day). The administration of regorafenib was discontinued after PCI for ST in the LAD, and aspirin and ticagrelor were discontinued 1 and 2 months later, respectively. No further thromboembolic events (including definite/probable ST) were observed, and heart failure was managed well. However, he died due to the progression of metastatic colorectal carcinoma about 3 months after ST onset.Fig. 1 Percutaneous coronary intervention for left anterior descending artery under intravascular ultrasound guidance. a, b Severe stenosis in the left anterior descending (LAD) artery (arrowhead) on initial coronary angiography (CAG). c Stent implantation in the LAD. d–g Final CAG showing an optimal result, with longitudinal and cross-sectional views in intravascular ultrasound imaging; acceptable stent expansion is confirmed
Fig. 2 Early stent thrombosis and revascularization. a Focal and eccentric contrastive defect in the previous left anterior descending stent. b–e Cross-sectional and longitudinal views of the stent thrombosis in optical frequency domain imaging (OFDI). f 3.5-mm perfusion balloon is dilated for 3 min. g Final coronary angiography reveals reduction of the contrastive defect and thrombolysis in myocardial infarction flow grade 3 without distal emboli. h–k Cross-sectional and longitudinal views in OFDI showing an increase in the lumen area and a small amount of residual thrombus
Discussion and conclusions
In this modern stent-based PCI era, ST represents a fatal and life-threatening complication. According to previous reports, the risk of ST is strongly associated with both, the patient background and procedural aspects [1, 3]. Certain patient background factors are independent predictors of a bleeding risk; malignant disease is a strong risk factor for major bleeding after PCI, as well as ST [1]. Our patient was classified as having a high thrombotic (4 points: anemia, heart failure, diabetes mellitus) and bleeding (4 points: heart failure, prior myocardial infarction, malignancy) risk, according to the CREDO-Kyoto thrombotic and bleeding risk scores [3]. Thus, we always had to consider the tradeoffs between the thrombotic and bleeding risks and PCI while caring for him.
The most frequent optical coherence tomography findings in early ST (within 30 days after index PCI) are uncovered struts and under-expansion [4]. Incomplete neointimal coverage of the struts in the early phase is normal, but the risk of ST associated with this procedure needs to be minimized. This risk could be reduced by optimizing stent placement with intracoronary imaging techniques and developing newer DES technology [1]. Moreover, dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor blocker after coronary stent implantation has been effective in preventing ST, and has been the standard treatment. Regarding P2Y12 receptor blockers, prasugrel or ticagrelor, in combination with aspirin, has been associated with a greater reduction in ST as compared to a combination of clopidogrel and aspirin [5, 6]. Furthermore, among stented patients with acute coronary syndrome treated by DAPT, low-dose rivaroxaban administration has been associated with a reduction in ST [7]. Thus, antithrombotic therapy after PCI has been established worldwide, but the optimal duration of DAPT remains controversial. Recent global guidelines recommend a shorter duration of DAPT for clinical efficacy. Additionally, it is recommended that the duration of the combination of triple antithrombotic therapy with DAPT and oral anticoagulants be as brief as possible [8]. However, there remains a lack of discussion regarding an appropriate antiplatelet therapy after PCI for cancer patients who are or are not undergoing chemotherapy. In our patient, although new-generation DES implantation was optimized by IVUS and a more potent antithrombotic therapy (DAPT and direct oral anticoagulant [DOAC]) was continued, early ST still occurred. This suggests that a standardized antithrombotic drug reduction may cause life-threatening ST in cancer patients receiving chemotherapy. The patient in our case was managed by changing the P2Y12 receptor blocker, increasing the DOAC dose, and withdrawing regorafenib until an adequate neointimal coverage of the struts was achieved. Thus, the risk of ST and the optimal duration of DAPT in cancer patients undergoing chemotherapy should be explored further.
While the association between venous thromboembolism (VTE) and malignancy is well-discussed, arterial thrombosis has more recently been recognized as a serious complication of cancer and chemotherapy. One study, based on a large database in the USA, reported that the incidence of arterial thromboembolic events (ATEs) in patients with cancer at 6 months was 4.7% [9]; patients with lung, gastric, or pancreatic cancers had the highest rates of ATEs (8.3, 6.5, and 5.9%, respectively). Moreover, an advanced stage of cancer was associated with a significant increase in the incidence of ATEs (stage 0 vs. stage 4: 2.3% vs. 7.7% at 6 months). Furthermore, certain chemotherapeutic agents, including VEGF inhibitors, have been reported to be associated with ATEs [10]; cisplatin, nilotinib, ponatinib, 5-FU, and capecitabine are particularly associated with a high incidence of coronary artery thrombotic events. Thus, while determining the risk of ischemic events after PCI, physicians should take into account the type of cancer, progression, and chemotherapeutic regimen. Similarly, the risks of occurrence and recurrence of cancer-associated VTE were found to vary according to the type and spread of the malignant disease [11]. Recent clinical trials assessing DOACs for cancer-associated VTE reported that DOACs seemed to be a reasonable treatment for VTE in such patients [12]. However, it should be noted that in these trials, bleeding events occurred in cases with gastrointestinal and urological tumors; such an occurrence of bleeding events in different types of cancers may also apply to DAPT after PCI in cancer patients. The traditional stratification of risks for bleeding and ischemic events after coronary stent implantation may need to be supplemented with information on the cancer type, progression, and chemotherapeutic regimen.
Regorafenib, an oral multi-targeted receptor tyrosine kinase inhibitor that targets VEGF (thereby affecting cell proliferation and angiogenesis), has been indicated for metastatic colorectal carcinoma. However, it is associated with cardiovascular complications such as hypertension, hemorrhage, thrombosis, and heart failure [2, 10, 13]. Regorafenib was previously reported to be less involved in thrombosis as compared to similar drugs, and has been relatively well-tolerated by patients [13]. However, increased platelet activation, endothelial dysfunction, and dysfunctional nitric oxide metabolism due to VEGF inhibitors result in thrombosis, because VEGF is an important signaling factor for endothelial cell health, which is essential for blood vessel formation and maintenance [10]. Thus, VEGF is important for endothelial cell health and vascular repair in patients undergoing PCI. As a result, VEGF inhibitors, such as regorafenib, might be associated with ST. In our case, it was important to consider a change in the chemotherapeutic regimen before PCI. However, the patient wished to continue regorafenib, because it was an almost final-line treatment for his cancer. Oncology and cardiovascular experts should make every effort to provide optimal medical care while respecting the patients' wishes.
The management of hemodynamically significant CAD in cancer patients, especially those undergoing chemotherapy, has not been fully established. Optimal stent replacement during PCI under intracoronary imaging could reduce the risk of ST, but this may be insufficient. The optimal treatment strategy for cancer patients with CAD, including invasive revascularization, antithrombotic therapy, and chemotherapy, needs to be verified. Future developments in the field of cardio-oncology will need to adapt to changes in the patient population and focus on optimal prevention and surveillance strategies accordingly.
Abbreviations
ATEsarterial thromboembolic events
BNPB-type natriuretic peptide
CADcoronary artery disease
CAGcoronary angiography
DAPTdual-antiplatelet therapy
DESdrug-eluting stent
DOACdirect oral anticoagulant
DVTdeep venous thrombosis
HLhigh-lateral
OFDIoptical frequency domain imaging
IVUSintravascular ultrasound imaging
LADleft anterior descending
PCIpercutaneous coronary intervention
STstent thrombosis
VEGFvascular endothelial growth factor
VTEvenous thromboembolism
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KS and TO managed the patient and wrote and revised the manuscript. KY, KZ and SM revised the manuscript and figures. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and in its additional files.
Ethics approval and consent to participate
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or with comparable ethical standards.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images and videos. A copy of the written consent is available for review by the editor of this journal.
Competing interests
The authors declare that they have no competing interests. | AMLODIPINE BESYLATE, APIXABAN, ASPIRIN, BISOPROLOL, ENALAPRIL, ESOMEPRAZOLE MAGNESIUM, FUROSEMIDE, INSULIN DEGLUDEC, MITIGLINIDE, PRASUGREL HYDROCHLORIDE, REGORAFENIB, SITAGLIPTIN | DrugsGivenReaction | CC BY | 33516171 | 18,873,767 | 2021-01-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Colorectal cancer'. | Early stent thrombosis confirmed in a cancer patient receiving regorafenib, despite triple antithrombotic therapy: a case report.
While developments in oncology have lengthened survival in patients with cancer, such patients often develop cardiovascular diseases. Thus, percutaneous coronary intervention (PCI) is frequently undertaken in them. Although stent thrombosis remains a fatal complication in stent-based PCI, worldwide consensus panels tend to recommend shorter duration of dual-antiplatelet therapy. This is based on its clinical efficacy that has resulted from technological innovation. However, there is insufficient discussion on the risk of stent thrombosis in cancer patients with coronary artery disease, especially in those undergoing chemotherapeutic regimens that have a risk for thrombosis, such as regimens with the anti-vascular endothelial growth factor. Presented here is a case of early stent thrombosis that occurred in a cancer patient on regorafenib, despite the administration of triple antithrombotic therapy. Case presentation A 66-year-old Japanese male patient received regorafenib for metastatic colorectal carcinoma and apixaban for deep vein thrombosis. Coronary angiography revealed severe stenosis in the proximal left anterior descending artery. A sirolimus-eluting stent was implanted, without malapposition and under-expansion, under intravascular ultrasound guidance while administering a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day). However, he was admitted to the hospital for exacerbation of heart failure 1 month after PCI. Coronary angiography revealed contrastive defects in the previous stent. Optical frequency domain imaging confirmed stent thrombosis. PCI was successfully performed with perfusion balloon long-inflation. Antithrombotic therapy was enhanced (aspirin: 100 mg/day, ticagrelor: 120 mg/day, and apixaban: 10 mg/day) and regorafenib was discontinued permanently. While ischemic events did not occur thereafter, the patient died due to metastatic carcinoma progression.
This case suggests that anti-vascular endothelial growth factor might contribute to early stent thrombosis, despite triple antithrombotic therapy. Further discussion is needed on the surveillance and management of cancer patients with coronary artery disease receiving chemotherapy, which carries a risk of thrombosis.
Background
Cardio-oncology is a rapidly growing subspeciality worldwide. Recent oncological developments have led to favorable clinical outcomes in cancer patients; however, many cancer survivors develop cardiovascular diseases. As a result, percutaneous coronary intervention (PCI) is frequently performed in cancer patients, who also develop coronary artery disease (CAD) while receiving chemotherapy.
Stent thrombosis (ST) is a rare but serious complication of PCI. Malignant disease is known as a strong risk factor for the development of ST and hemorrhage after stent implantation [1]. In addition, many modern chemotherapies are associated with vascular complications such as thrombosis and major bleeding [2]. Cancer and its treatment with chemotherapy are associated with a potential risk of thrombotic and bleeding complications in patients undergoing PCI. However, currently, there is insufficient evidence for optimal prevention and risk stratification of ST in these patients.
Described below is a case of early ST that was confirmed by optical frequency domain imaging (OFDI). In this case, ST occurred in a cancer patient receiving anti-vascular endothelial growth factor (VEGF) therapy in our hospital despite the administration of a triple antithrombotic therapy.
Case presentation
A 66-year-old Japanese male patient had received regorafenib (160 mg/day) as an anticancer treatment for metastatic colorectal carcinoma. His medical history included hypertension, diabetes mellitus, dyslipidemia, chronic heart failure, deep vein thrombosis (DVT), and permanent pacemaker implantation due to complete atrioventricular block. His DVT had been managed with low-dose apixaban (5 mg/day; body weight: 75 kg, creatinine: 1.0 mg/dL) to avoid bleeding complications.
Two months ago, he had suffered from non-ST-elevation myocardial infarction with the high-lateral (HL) branch as the culprit lesion, accompanied by chest discomfort; the HL branch occlusion was treated with balloon dilation only to avoid the need of a long-term triple antithrombotic therapy. At the same time, coronary angiography (CAG) revealed severe stenosis in the proximal left anterior descending (LAD) artery. A fractional flow reserve value of 0.72 confirmed a physiologically significant lesion. After PCI for the HL branch, regorafenib was withdrawn temporarily, and a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day) was successfully continued for two months without bleeding complications. Subsequently, the patient underwent PCI for severe stenosis in the LAD lesion two months after PCI for HL, as he demonstrated good tolerance to the triple antithrombotic therapy. Other medications administered included bisoprolol (1.25 mg/day), enalapril (2.5 mg/day), furosemide (20 mg/day), esomeprazole (20 mg/day), amlodipine (5 mg/day), sitagliptin (50 mg/day), mitiglinide (30 mg/day), and insulin degludec (9 units). In addition, routine blood testing revealed an elevated level of B-type natriuretic peptide (BNP), normal kidney function, high value of HbA1c, and mild anemia (BNP: 191.6 pg/mL, creatinine: 0.68 mg/dL, estimated glomerular filtration rate: 89.3 mL/minute/1.73 m2, HbA1c: 8.4%, hemoglobin: 9.9 g/dL, and platelet count: 318 × 103/µL). He was classified as having a high thrombotic and bleeding risk at this time, according to the CREDO-Kyoto thrombotic and bleeding risk scores. A sirolimus-eluting stent, which is a drug-eluting stent (DES) (Ultimaster Tansei 3.5/38 mm; Terumo Corporation, Tokyo, Japan), was implanted in the LAD lesion without malapposition or significant under-expansion, as confirmed by intravascular ultrasound imaging (IVUS) analysis (Fig. 1). After PCI for the LAD, regorafenib was resumed because it exhibited a clinical effect on the patient's cancer. Nevertheless, the patient was admitted to our hospital for congestive heart failure with dyspnea one month later (BNP: 1,512.5 pg/mL). Echocardiography demonstrated new severe hypokinesis of the anteroseptal wall and apex. Despite continued triple antithrombotic therapy, CAG revealed focal and eccentric contrastive defects in the previous LAD stent, and OFDI confirmed ST (Fig. 2a–e). A 3.5/20 mm perfusion balloon (Ryusei, Kaneka Medical, Tokyo, Japan) was inflated for 3 min using an embolic protection device (Fig. 2f). CAG and OFDI confirmed optimal initial gain in the ST site and thrombolysis in myocardial infarction flow grade 3, with no complications including distal emboli (Fig. 2g–k). Antithrombotic therapy was further enhanced temporarily to prevent the recurrence of ST; it included aspirin (100 mg/day), ticagrelor (120 mg/day), and apixaban (10 mg/day). The administration of regorafenib was discontinued after PCI for ST in the LAD, and aspirin and ticagrelor were discontinued 1 and 2 months later, respectively. No further thromboembolic events (including definite/probable ST) were observed, and heart failure was managed well. However, he died due to the progression of metastatic colorectal carcinoma about 3 months after ST onset.Fig. 1 Percutaneous coronary intervention for left anterior descending artery under intravascular ultrasound guidance. a, b Severe stenosis in the left anterior descending (LAD) artery (arrowhead) on initial coronary angiography (CAG). c Stent implantation in the LAD. d–g Final CAG showing an optimal result, with longitudinal and cross-sectional views in intravascular ultrasound imaging; acceptable stent expansion is confirmed
Fig. 2 Early stent thrombosis and revascularization. a Focal and eccentric contrastive defect in the previous left anterior descending stent. b–e Cross-sectional and longitudinal views of the stent thrombosis in optical frequency domain imaging (OFDI). f 3.5-mm perfusion balloon is dilated for 3 min. g Final coronary angiography reveals reduction of the contrastive defect and thrombolysis in myocardial infarction flow grade 3 without distal emboli. h–k Cross-sectional and longitudinal views in OFDI showing an increase in the lumen area and a small amount of residual thrombus
Discussion and conclusions
In this modern stent-based PCI era, ST represents a fatal and life-threatening complication. According to previous reports, the risk of ST is strongly associated with both, the patient background and procedural aspects [1, 3]. Certain patient background factors are independent predictors of a bleeding risk; malignant disease is a strong risk factor for major bleeding after PCI, as well as ST [1]. Our patient was classified as having a high thrombotic (4 points: anemia, heart failure, diabetes mellitus) and bleeding (4 points: heart failure, prior myocardial infarction, malignancy) risk, according to the CREDO-Kyoto thrombotic and bleeding risk scores [3]. Thus, we always had to consider the tradeoffs between the thrombotic and bleeding risks and PCI while caring for him.
The most frequent optical coherence tomography findings in early ST (within 30 days after index PCI) are uncovered struts and under-expansion [4]. Incomplete neointimal coverage of the struts in the early phase is normal, but the risk of ST associated with this procedure needs to be minimized. This risk could be reduced by optimizing stent placement with intracoronary imaging techniques and developing newer DES technology [1]. Moreover, dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor blocker after coronary stent implantation has been effective in preventing ST, and has been the standard treatment. Regarding P2Y12 receptor blockers, prasugrel or ticagrelor, in combination with aspirin, has been associated with a greater reduction in ST as compared to a combination of clopidogrel and aspirin [5, 6]. Furthermore, among stented patients with acute coronary syndrome treated by DAPT, low-dose rivaroxaban administration has been associated with a reduction in ST [7]. Thus, antithrombotic therapy after PCI has been established worldwide, but the optimal duration of DAPT remains controversial. Recent global guidelines recommend a shorter duration of DAPT for clinical efficacy. Additionally, it is recommended that the duration of the combination of triple antithrombotic therapy with DAPT and oral anticoagulants be as brief as possible [8]. However, there remains a lack of discussion regarding an appropriate antiplatelet therapy after PCI for cancer patients who are or are not undergoing chemotherapy. In our patient, although new-generation DES implantation was optimized by IVUS and a more potent antithrombotic therapy (DAPT and direct oral anticoagulant [DOAC]) was continued, early ST still occurred. This suggests that a standardized antithrombotic drug reduction may cause life-threatening ST in cancer patients receiving chemotherapy. The patient in our case was managed by changing the P2Y12 receptor blocker, increasing the DOAC dose, and withdrawing regorafenib until an adequate neointimal coverage of the struts was achieved. Thus, the risk of ST and the optimal duration of DAPT in cancer patients undergoing chemotherapy should be explored further.
While the association between venous thromboembolism (VTE) and malignancy is well-discussed, arterial thrombosis has more recently been recognized as a serious complication of cancer and chemotherapy. One study, based on a large database in the USA, reported that the incidence of arterial thromboembolic events (ATEs) in patients with cancer at 6 months was 4.7% [9]; patients with lung, gastric, or pancreatic cancers had the highest rates of ATEs (8.3, 6.5, and 5.9%, respectively). Moreover, an advanced stage of cancer was associated with a significant increase in the incidence of ATEs (stage 0 vs. stage 4: 2.3% vs. 7.7% at 6 months). Furthermore, certain chemotherapeutic agents, including VEGF inhibitors, have been reported to be associated with ATEs [10]; cisplatin, nilotinib, ponatinib, 5-FU, and capecitabine are particularly associated with a high incidence of coronary artery thrombotic events. Thus, while determining the risk of ischemic events after PCI, physicians should take into account the type of cancer, progression, and chemotherapeutic regimen. Similarly, the risks of occurrence and recurrence of cancer-associated VTE were found to vary according to the type and spread of the malignant disease [11]. Recent clinical trials assessing DOACs for cancer-associated VTE reported that DOACs seemed to be a reasonable treatment for VTE in such patients [12]. However, it should be noted that in these trials, bleeding events occurred in cases with gastrointestinal and urological tumors; such an occurrence of bleeding events in different types of cancers may also apply to DAPT after PCI in cancer patients. The traditional stratification of risks for bleeding and ischemic events after coronary stent implantation may need to be supplemented with information on the cancer type, progression, and chemotherapeutic regimen.
Regorafenib, an oral multi-targeted receptor tyrosine kinase inhibitor that targets VEGF (thereby affecting cell proliferation and angiogenesis), has been indicated for metastatic colorectal carcinoma. However, it is associated with cardiovascular complications such as hypertension, hemorrhage, thrombosis, and heart failure [2, 10, 13]. Regorafenib was previously reported to be less involved in thrombosis as compared to similar drugs, and has been relatively well-tolerated by patients [13]. However, increased platelet activation, endothelial dysfunction, and dysfunctional nitric oxide metabolism due to VEGF inhibitors result in thrombosis, because VEGF is an important signaling factor for endothelial cell health, which is essential for blood vessel formation and maintenance [10]. Thus, VEGF is important for endothelial cell health and vascular repair in patients undergoing PCI. As a result, VEGF inhibitors, such as regorafenib, might be associated with ST. In our case, it was important to consider a change in the chemotherapeutic regimen before PCI. However, the patient wished to continue regorafenib, because it was an almost final-line treatment for his cancer. Oncology and cardiovascular experts should make every effort to provide optimal medical care while respecting the patients' wishes.
The management of hemodynamically significant CAD in cancer patients, especially those undergoing chemotherapy, has not been fully established. Optimal stent replacement during PCI under intracoronary imaging could reduce the risk of ST, but this may be insufficient. The optimal treatment strategy for cancer patients with CAD, including invasive revascularization, antithrombotic therapy, and chemotherapy, needs to be verified. Future developments in the field of cardio-oncology will need to adapt to changes in the patient population and focus on optimal prevention and surveillance strategies accordingly.
Abbreviations
ATEsarterial thromboembolic events
BNPB-type natriuretic peptide
CADcoronary artery disease
CAGcoronary angiography
DAPTdual-antiplatelet therapy
DESdrug-eluting stent
DOACdirect oral anticoagulant
DVTdeep venous thrombosis
HLhigh-lateral
OFDIoptical frequency domain imaging
IVUSintravascular ultrasound imaging
LADleft anterior descending
PCIpercutaneous coronary intervention
STstent thrombosis
VEGFvascular endothelial growth factor
VTEvenous thromboembolism
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KS and TO managed the patient and wrote and revised the manuscript. KY, KZ and SM revised the manuscript and figures. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and in its additional files.
Ethics approval and consent to participate
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or with comparable ethical standards.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images and videos. A copy of the written consent is available for review by the editor of this journal.
Competing interests
The authors declare that they have no competing interests. | AMLODIPINE BESYLATE, APIXABAN, ASPIRIN, BISOPROLOL, ENALAPRIL, ESOMEPRAZOLE MAGNESIUM, FUROSEMIDE, INSULIN DEGLUDEC, MITIGLINIDE, PRASUGREL HYDROCHLORIDE, REGORAFENIB, SITAGLIPTIN | DrugsGivenReaction | CC BY | 33516171 | 18,873,767 | 2021-01-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Early stent thrombosis confirmed in a cancer patient receiving regorafenib, despite triple antithrombotic therapy: a case report.
While developments in oncology have lengthened survival in patients with cancer, such patients often develop cardiovascular diseases. Thus, percutaneous coronary intervention (PCI) is frequently undertaken in them. Although stent thrombosis remains a fatal complication in stent-based PCI, worldwide consensus panels tend to recommend shorter duration of dual-antiplatelet therapy. This is based on its clinical efficacy that has resulted from technological innovation. However, there is insufficient discussion on the risk of stent thrombosis in cancer patients with coronary artery disease, especially in those undergoing chemotherapeutic regimens that have a risk for thrombosis, such as regimens with the anti-vascular endothelial growth factor. Presented here is a case of early stent thrombosis that occurred in a cancer patient on regorafenib, despite the administration of triple antithrombotic therapy. Case presentation A 66-year-old Japanese male patient received regorafenib for metastatic colorectal carcinoma and apixaban for deep vein thrombosis. Coronary angiography revealed severe stenosis in the proximal left anterior descending artery. A sirolimus-eluting stent was implanted, without malapposition and under-expansion, under intravascular ultrasound guidance while administering a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day). However, he was admitted to the hospital for exacerbation of heart failure 1 month after PCI. Coronary angiography revealed contrastive defects in the previous stent. Optical frequency domain imaging confirmed stent thrombosis. PCI was successfully performed with perfusion balloon long-inflation. Antithrombotic therapy was enhanced (aspirin: 100 mg/day, ticagrelor: 120 mg/day, and apixaban: 10 mg/day) and regorafenib was discontinued permanently. While ischemic events did not occur thereafter, the patient died due to metastatic carcinoma progression.
This case suggests that anti-vascular endothelial growth factor might contribute to early stent thrombosis, despite triple antithrombotic therapy. Further discussion is needed on the surveillance and management of cancer patients with coronary artery disease receiving chemotherapy, which carries a risk of thrombosis.
Background
Cardio-oncology is a rapidly growing subspeciality worldwide. Recent oncological developments have led to favorable clinical outcomes in cancer patients; however, many cancer survivors develop cardiovascular diseases. As a result, percutaneous coronary intervention (PCI) is frequently performed in cancer patients, who also develop coronary artery disease (CAD) while receiving chemotherapy.
Stent thrombosis (ST) is a rare but serious complication of PCI. Malignant disease is known as a strong risk factor for the development of ST and hemorrhage after stent implantation [1]. In addition, many modern chemotherapies are associated with vascular complications such as thrombosis and major bleeding [2]. Cancer and its treatment with chemotherapy are associated with a potential risk of thrombotic and bleeding complications in patients undergoing PCI. However, currently, there is insufficient evidence for optimal prevention and risk stratification of ST in these patients.
Described below is a case of early ST that was confirmed by optical frequency domain imaging (OFDI). In this case, ST occurred in a cancer patient receiving anti-vascular endothelial growth factor (VEGF) therapy in our hospital despite the administration of a triple antithrombotic therapy.
Case presentation
A 66-year-old Japanese male patient had received regorafenib (160 mg/day) as an anticancer treatment for metastatic colorectal carcinoma. His medical history included hypertension, diabetes mellitus, dyslipidemia, chronic heart failure, deep vein thrombosis (DVT), and permanent pacemaker implantation due to complete atrioventricular block. His DVT had been managed with low-dose apixaban (5 mg/day; body weight: 75 kg, creatinine: 1.0 mg/dL) to avoid bleeding complications.
Two months ago, he had suffered from non-ST-elevation myocardial infarction with the high-lateral (HL) branch as the culprit lesion, accompanied by chest discomfort; the HL branch occlusion was treated with balloon dilation only to avoid the need of a long-term triple antithrombotic therapy. At the same time, coronary angiography (CAG) revealed severe stenosis in the proximal left anterior descending (LAD) artery. A fractional flow reserve value of 0.72 confirmed a physiologically significant lesion. After PCI for the HL branch, regorafenib was withdrawn temporarily, and a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day) was successfully continued for two months without bleeding complications. Subsequently, the patient underwent PCI for severe stenosis in the LAD lesion two months after PCI for HL, as he demonstrated good tolerance to the triple antithrombotic therapy. Other medications administered included bisoprolol (1.25 mg/day), enalapril (2.5 mg/day), furosemide (20 mg/day), esomeprazole (20 mg/day), amlodipine (5 mg/day), sitagliptin (50 mg/day), mitiglinide (30 mg/day), and insulin degludec (9 units). In addition, routine blood testing revealed an elevated level of B-type natriuretic peptide (BNP), normal kidney function, high value of HbA1c, and mild anemia (BNP: 191.6 pg/mL, creatinine: 0.68 mg/dL, estimated glomerular filtration rate: 89.3 mL/minute/1.73 m2, HbA1c: 8.4%, hemoglobin: 9.9 g/dL, and platelet count: 318 × 103/µL). He was classified as having a high thrombotic and bleeding risk at this time, according to the CREDO-Kyoto thrombotic and bleeding risk scores. A sirolimus-eluting stent, which is a drug-eluting stent (DES) (Ultimaster Tansei 3.5/38 mm; Terumo Corporation, Tokyo, Japan), was implanted in the LAD lesion without malapposition or significant under-expansion, as confirmed by intravascular ultrasound imaging (IVUS) analysis (Fig. 1). After PCI for the LAD, regorafenib was resumed because it exhibited a clinical effect on the patient's cancer. Nevertheless, the patient was admitted to our hospital for congestive heart failure with dyspnea one month later (BNP: 1,512.5 pg/mL). Echocardiography demonstrated new severe hypokinesis of the anteroseptal wall and apex. Despite continued triple antithrombotic therapy, CAG revealed focal and eccentric contrastive defects in the previous LAD stent, and OFDI confirmed ST (Fig. 2a–e). A 3.5/20 mm perfusion balloon (Ryusei, Kaneka Medical, Tokyo, Japan) was inflated for 3 min using an embolic protection device (Fig. 2f). CAG and OFDI confirmed optimal initial gain in the ST site and thrombolysis in myocardial infarction flow grade 3, with no complications including distal emboli (Fig. 2g–k). Antithrombotic therapy was further enhanced temporarily to prevent the recurrence of ST; it included aspirin (100 mg/day), ticagrelor (120 mg/day), and apixaban (10 mg/day). The administration of regorafenib was discontinued after PCI for ST in the LAD, and aspirin and ticagrelor were discontinued 1 and 2 months later, respectively. No further thromboembolic events (including definite/probable ST) were observed, and heart failure was managed well. However, he died due to the progression of metastatic colorectal carcinoma about 3 months after ST onset.Fig. 1 Percutaneous coronary intervention for left anterior descending artery under intravascular ultrasound guidance. a, b Severe stenosis in the left anterior descending (LAD) artery (arrowhead) on initial coronary angiography (CAG). c Stent implantation in the LAD. d–g Final CAG showing an optimal result, with longitudinal and cross-sectional views in intravascular ultrasound imaging; acceptable stent expansion is confirmed
Fig. 2 Early stent thrombosis and revascularization. a Focal and eccentric contrastive defect in the previous left anterior descending stent. b–e Cross-sectional and longitudinal views of the stent thrombosis in optical frequency domain imaging (OFDI). f 3.5-mm perfusion balloon is dilated for 3 min. g Final coronary angiography reveals reduction of the contrastive defect and thrombolysis in myocardial infarction flow grade 3 without distal emboli. h–k Cross-sectional and longitudinal views in OFDI showing an increase in the lumen area and a small amount of residual thrombus
Discussion and conclusions
In this modern stent-based PCI era, ST represents a fatal and life-threatening complication. According to previous reports, the risk of ST is strongly associated with both, the patient background and procedural aspects [1, 3]. Certain patient background factors are independent predictors of a bleeding risk; malignant disease is a strong risk factor for major bleeding after PCI, as well as ST [1]. Our patient was classified as having a high thrombotic (4 points: anemia, heart failure, diabetes mellitus) and bleeding (4 points: heart failure, prior myocardial infarction, malignancy) risk, according to the CREDO-Kyoto thrombotic and bleeding risk scores [3]. Thus, we always had to consider the tradeoffs between the thrombotic and bleeding risks and PCI while caring for him.
The most frequent optical coherence tomography findings in early ST (within 30 days after index PCI) are uncovered struts and under-expansion [4]. Incomplete neointimal coverage of the struts in the early phase is normal, but the risk of ST associated with this procedure needs to be minimized. This risk could be reduced by optimizing stent placement with intracoronary imaging techniques and developing newer DES technology [1]. Moreover, dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor blocker after coronary stent implantation has been effective in preventing ST, and has been the standard treatment. Regarding P2Y12 receptor blockers, prasugrel or ticagrelor, in combination with aspirin, has been associated with a greater reduction in ST as compared to a combination of clopidogrel and aspirin [5, 6]. Furthermore, among stented patients with acute coronary syndrome treated by DAPT, low-dose rivaroxaban administration has been associated with a reduction in ST [7]. Thus, antithrombotic therapy after PCI has been established worldwide, but the optimal duration of DAPT remains controversial. Recent global guidelines recommend a shorter duration of DAPT for clinical efficacy. Additionally, it is recommended that the duration of the combination of triple antithrombotic therapy with DAPT and oral anticoagulants be as brief as possible [8]. However, there remains a lack of discussion regarding an appropriate antiplatelet therapy after PCI for cancer patients who are or are not undergoing chemotherapy. In our patient, although new-generation DES implantation was optimized by IVUS and a more potent antithrombotic therapy (DAPT and direct oral anticoagulant [DOAC]) was continued, early ST still occurred. This suggests that a standardized antithrombotic drug reduction may cause life-threatening ST in cancer patients receiving chemotherapy. The patient in our case was managed by changing the P2Y12 receptor blocker, increasing the DOAC dose, and withdrawing regorafenib until an adequate neointimal coverage of the struts was achieved. Thus, the risk of ST and the optimal duration of DAPT in cancer patients undergoing chemotherapy should be explored further.
While the association between venous thromboembolism (VTE) and malignancy is well-discussed, arterial thrombosis has more recently been recognized as a serious complication of cancer and chemotherapy. One study, based on a large database in the USA, reported that the incidence of arterial thromboembolic events (ATEs) in patients with cancer at 6 months was 4.7% [9]; patients with lung, gastric, or pancreatic cancers had the highest rates of ATEs (8.3, 6.5, and 5.9%, respectively). Moreover, an advanced stage of cancer was associated with a significant increase in the incidence of ATEs (stage 0 vs. stage 4: 2.3% vs. 7.7% at 6 months). Furthermore, certain chemotherapeutic agents, including VEGF inhibitors, have been reported to be associated with ATEs [10]; cisplatin, nilotinib, ponatinib, 5-FU, and capecitabine are particularly associated with a high incidence of coronary artery thrombotic events. Thus, while determining the risk of ischemic events after PCI, physicians should take into account the type of cancer, progression, and chemotherapeutic regimen. Similarly, the risks of occurrence and recurrence of cancer-associated VTE were found to vary according to the type and spread of the malignant disease [11]. Recent clinical trials assessing DOACs for cancer-associated VTE reported that DOACs seemed to be a reasonable treatment for VTE in such patients [12]. However, it should be noted that in these trials, bleeding events occurred in cases with gastrointestinal and urological tumors; such an occurrence of bleeding events in different types of cancers may also apply to DAPT after PCI in cancer patients. The traditional stratification of risks for bleeding and ischemic events after coronary stent implantation may need to be supplemented with information on the cancer type, progression, and chemotherapeutic regimen.
Regorafenib, an oral multi-targeted receptor tyrosine kinase inhibitor that targets VEGF (thereby affecting cell proliferation and angiogenesis), has been indicated for metastatic colorectal carcinoma. However, it is associated with cardiovascular complications such as hypertension, hemorrhage, thrombosis, and heart failure [2, 10, 13]. Regorafenib was previously reported to be less involved in thrombosis as compared to similar drugs, and has been relatively well-tolerated by patients [13]. However, increased platelet activation, endothelial dysfunction, and dysfunctional nitric oxide metabolism due to VEGF inhibitors result in thrombosis, because VEGF is an important signaling factor for endothelial cell health, which is essential for blood vessel formation and maintenance [10]. Thus, VEGF is important for endothelial cell health and vascular repair in patients undergoing PCI. As a result, VEGF inhibitors, such as regorafenib, might be associated with ST. In our case, it was important to consider a change in the chemotherapeutic regimen before PCI. However, the patient wished to continue regorafenib, because it was an almost final-line treatment for his cancer. Oncology and cardiovascular experts should make every effort to provide optimal medical care while respecting the patients' wishes.
The management of hemodynamically significant CAD in cancer patients, especially those undergoing chemotherapy, has not been fully established. Optimal stent replacement during PCI under intracoronary imaging could reduce the risk of ST, but this may be insufficient. The optimal treatment strategy for cancer patients with CAD, including invasive revascularization, antithrombotic therapy, and chemotherapy, needs to be verified. Future developments in the field of cardio-oncology will need to adapt to changes in the patient population and focus on optimal prevention and surveillance strategies accordingly.
Abbreviations
ATEsarterial thromboembolic events
BNPB-type natriuretic peptide
CADcoronary artery disease
CAGcoronary angiography
DAPTdual-antiplatelet therapy
DESdrug-eluting stent
DOACdirect oral anticoagulant
DVTdeep venous thrombosis
HLhigh-lateral
OFDIoptical frequency domain imaging
IVUSintravascular ultrasound imaging
LADleft anterior descending
PCIpercutaneous coronary intervention
STstent thrombosis
VEGFvascular endothelial growth factor
VTEvenous thromboembolism
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KS and TO managed the patient and wrote and revised the manuscript. KY, KZ and SM revised the manuscript and figures. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and in its additional files.
Ethics approval and consent to participate
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or with comparable ethical standards.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images and videos. A copy of the written consent is available for review by the editor of this journal.
Competing interests
The authors declare that they have no competing interests. | AMLODIPINE BESYLATE, APIXABAN, ASPIRIN, BISOPROLOL, ENALAPRIL, ESOMEPRAZOLE MAGNESIUM, FUROSEMIDE, INSULIN DEGLUDEC, MITIGLINIDE, PRASUGREL, REGORAFENIB, SITAGLIPTIN | DrugsGivenReaction | CC BY | 33516171 | 18,888,660 | 2021-01-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Glycosylated haemoglobin increased'. | Early stent thrombosis confirmed in a cancer patient receiving regorafenib, despite triple antithrombotic therapy: a case report.
While developments in oncology have lengthened survival in patients with cancer, such patients often develop cardiovascular diseases. Thus, percutaneous coronary intervention (PCI) is frequently undertaken in them. Although stent thrombosis remains a fatal complication in stent-based PCI, worldwide consensus panels tend to recommend shorter duration of dual-antiplatelet therapy. This is based on its clinical efficacy that has resulted from technological innovation. However, there is insufficient discussion on the risk of stent thrombosis in cancer patients with coronary artery disease, especially in those undergoing chemotherapeutic regimens that have a risk for thrombosis, such as regimens with the anti-vascular endothelial growth factor. Presented here is a case of early stent thrombosis that occurred in a cancer patient on regorafenib, despite the administration of triple antithrombotic therapy. Case presentation A 66-year-old Japanese male patient received regorafenib for metastatic colorectal carcinoma and apixaban for deep vein thrombosis. Coronary angiography revealed severe stenosis in the proximal left anterior descending artery. A sirolimus-eluting stent was implanted, without malapposition and under-expansion, under intravascular ultrasound guidance while administering a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day). However, he was admitted to the hospital for exacerbation of heart failure 1 month after PCI. Coronary angiography revealed contrastive defects in the previous stent. Optical frequency domain imaging confirmed stent thrombosis. PCI was successfully performed with perfusion balloon long-inflation. Antithrombotic therapy was enhanced (aspirin: 100 mg/day, ticagrelor: 120 mg/day, and apixaban: 10 mg/day) and regorafenib was discontinued permanently. While ischemic events did not occur thereafter, the patient died due to metastatic carcinoma progression.
This case suggests that anti-vascular endothelial growth factor might contribute to early stent thrombosis, despite triple antithrombotic therapy. Further discussion is needed on the surveillance and management of cancer patients with coronary artery disease receiving chemotherapy, which carries a risk of thrombosis.
Background
Cardio-oncology is a rapidly growing subspeciality worldwide. Recent oncological developments have led to favorable clinical outcomes in cancer patients; however, many cancer survivors develop cardiovascular diseases. As a result, percutaneous coronary intervention (PCI) is frequently performed in cancer patients, who also develop coronary artery disease (CAD) while receiving chemotherapy.
Stent thrombosis (ST) is a rare but serious complication of PCI. Malignant disease is known as a strong risk factor for the development of ST and hemorrhage after stent implantation [1]. In addition, many modern chemotherapies are associated with vascular complications such as thrombosis and major bleeding [2]. Cancer and its treatment with chemotherapy are associated with a potential risk of thrombotic and bleeding complications in patients undergoing PCI. However, currently, there is insufficient evidence for optimal prevention and risk stratification of ST in these patients.
Described below is a case of early ST that was confirmed by optical frequency domain imaging (OFDI). In this case, ST occurred in a cancer patient receiving anti-vascular endothelial growth factor (VEGF) therapy in our hospital despite the administration of a triple antithrombotic therapy.
Case presentation
A 66-year-old Japanese male patient had received regorafenib (160 mg/day) as an anticancer treatment for metastatic colorectal carcinoma. His medical history included hypertension, diabetes mellitus, dyslipidemia, chronic heart failure, deep vein thrombosis (DVT), and permanent pacemaker implantation due to complete atrioventricular block. His DVT had been managed with low-dose apixaban (5 mg/day; body weight: 75 kg, creatinine: 1.0 mg/dL) to avoid bleeding complications.
Two months ago, he had suffered from non-ST-elevation myocardial infarction with the high-lateral (HL) branch as the culprit lesion, accompanied by chest discomfort; the HL branch occlusion was treated with balloon dilation only to avoid the need of a long-term triple antithrombotic therapy. At the same time, coronary angiography (CAG) revealed severe stenosis in the proximal left anterior descending (LAD) artery. A fractional flow reserve value of 0.72 confirmed a physiologically significant lesion. After PCI for the HL branch, regorafenib was withdrawn temporarily, and a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day) was successfully continued for two months without bleeding complications. Subsequently, the patient underwent PCI for severe stenosis in the LAD lesion two months after PCI for HL, as he demonstrated good tolerance to the triple antithrombotic therapy. Other medications administered included bisoprolol (1.25 mg/day), enalapril (2.5 mg/day), furosemide (20 mg/day), esomeprazole (20 mg/day), amlodipine (5 mg/day), sitagliptin (50 mg/day), mitiglinide (30 mg/day), and insulin degludec (9 units). In addition, routine blood testing revealed an elevated level of B-type natriuretic peptide (BNP), normal kidney function, high value of HbA1c, and mild anemia (BNP: 191.6 pg/mL, creatinine: 0.68 mg/dL, estimated glomerular filtration rate: 89.3 mL/minute/1.73 m2, HbA1c: 8.4%, hemoglobin: 9.9 g/dL, and platelet count: 318 × 103/µL). He was classified as having a high thrombotic and bleeding risk at this time, according to the CREDO-Kyoto thrombotic and bleeding risk scores. A sirolimus-eluting stent, which is a drug-eluting stent (DES) (Ultimaster Tansei 3.5/38 mm; Terumo Corporation, Tokyo, Japan), was implanted in the LAD lesion without malapposition or significant under-expansion, as confirmed by intravascular ultrasound imaging (IVUS) analysis (Fig. 1). After PCI for the LAD, regorafenib was resumed because it exhibited a clinical effect on the patient's cancer. Nevertheless, the patient was admitted to our hospital for congestive heart failure with dyspnea one month later (BNP: 1,512.5 pg/mL). Echocardiography demonstrated new severe hypokinesis of the anteroseptal wall and apex. Despite continued triple antithrombotic therapy, CAG revealed focal and eccentric contrastive defects in the previous LAD stent, and OFDI confirmed ST (Fig. 2a–e). A 3.5/20 mm perfusion balloon (Ryusei, Kaneka Medical, Tokyo, Japan) was inflated for 3 min using an embolic protection device (Fig. 2f). CAG and OFDI confirmed optimal initial gain in the ST site and thrombolysis in myocardial infarction flow grade 3, with no complications including distal emboli (Fig. 2g–k). Antithrombotic therapy was further enhanced temporarily to prevent the recurrence of ST; it included aspirin (100 mg/day), ticagrelor (120 mg/day), and apixaban (10 mg/day). The administration of regorafenib was discontinued after PCI for ST in the LAD, and aspirin and ticagrelor were discontinued 1 and 2 months later, respectively. No further thromboembolic events (including definite/probable ST) were observed, and heart failure was managed well. However, he died due to the progression of metastatic colorectal carcinoma about 3 months after ST onset.Fig. 1 Percutaneous coronary intervention for left anterior descending artery under intravascular ultrasound guidance. a, b Severe stenosis in the left anterior descending (LAD) artery (arrowhead) on initial coronary angiography (CAG). c Stent implantation in the LAD. d–g Final CAG showing an optimal result, with longitudinal and cross-sectional views in intravascular ultrasound imaging; acceptable stent expansion is confirmed
Fig. 2 Early stent thrombosis and revascularization. a Focal and eccentric contrastive defect in the previous left anterior descending stent. b–e Cross-sectional and longitudinal views of the stent thrombosis in optical frequency domain imaging (OFDI). f 3.5-mm perfusion balloon is dilated for 3 min. g Final coronary angiography reveals reduction of the contrastive defect and thrombolysis in myocardial infarction flow grade 3 without distal emboli. h–k Cross-sectional and longitudinal views in OFDI showing an increase in the lumen area and a small amount of residual thrombus
Discussion and conclusions
In this modern stent-based PCI era, ST represents a fatal and life-threatening complication. According to previous reports, the risk of ST is strongly associated with both, the patient background and procedural aspects [1, 3]. Certain patient background factors are independent predictors of a bleeding risk; malignant disease is a strong risk factor for major bleeding after PCI, as well as ST [1]. Our patient was classified as having a high thrombotic (4 points: anemia, heart failure, diabetes mellitus) and bleeding (4 points: heart failure, prior myocardial infarction, malignancy) risk, according to the CREDO-Kyoto thrombotic and bleeding risk scores [3]. Thus, we always had to consider the tradeoffs between the thrombotic and bleeding risks and PCI while caring for him.
The most frequent optical coherence tomography findings in early ST (within 30 days after index PCI) are uncovered struts and under-expansion [4]. Incomplete neointimal coverage of the struts in the early phase is normal, but the risk of ST associated with this procedure needs to be minimized. This risk could be reduced by optimizing stent placement with intracoronary imaging techniques and developing newer DES technology [1]. Moreover, dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor blocker after coronary stent implantation has been effective in preventing ST, and has been the standard treatment. Regarding P2Y12 receptor blockers, prasugrel or ticagrelor, in combination with aspirin, has been associated with a greater reduction in ST as compared to a combination of clopidogrel and aspirin [5, 6]. Furthermore, among stented patients with acute coronary syndrome treated by DAPT, low-dose rivaroxaban administration has been associated with a reduction in ST [7]. Thus, antithrombotic therapy after PCI has been established worldwide, but the optimal duration of DAPT remains controversial. Recent global guidelines recommend a shorter duration of DAPT for clinical efficacy. Additionally, it is recommended that the duration of the combination of triple antithrombotic therapy with DAPT and oral anticoagulants be as brief as possible [8]. However, there remains a lack of discussion regarding an appropriate antiplatelet therapy after PCI for cancer patients who are or are not undergoing chemotherapy. In our patient, although new-generation DES implantation was optimized by IVUS and a more potent antithrombotic therapy (DAPT and direct oral anticoagulant [DOAC]) was continued, early ST still occurred. This suggests that a standardized antithrombotic drug reduction may cause life-threatening ST in cancer patients receiving chemotherapy. The patient in our case was managed by changing the P2Y12 receptor blocker, increasing the DOAC dose, and withdrawing regorafenib until an adequate neointimal coverage of the struts was achieved. Thus, the risk of ST and the optimal duration of DAPT in cancer patients undergoing chemotherapy should be explored further.
While the association between venous thromboembolism (VTE) and malignancy is well-discussed, arterial thrombosis has more recently been recognized as a serious complication of cancer and chemotherapy. One study, based on a large database in the USA, reported that the incidence of arterial thromboembolic events (ATEs) in patients with cancer at 6 months was 4.7% [9]; patients with lung, gastric, or pancreatic cancers had the highest rates of ATEs (8.3, 6.5, and 5.9%, respectively). Moreover, an advanced stage of cancer was associated with a significant increase in the incidence of ATEs (stage 0 vs. stage 4: 2.3% vs. 7.7% at 6 months). Furthermore, certain chemotherapeutic agents, including VEGF inhibitors, have been reported to be associated with ATEs [10]; cisplatin, nilotinib, ponatinib, 5-FU, and capecitabine are particularly associated with a high incidence of coronary artery thrombotic events. Thus, while determining the risk of ischemic events after PCI, physicians should take into account the type of cancer, progression, and chemotherapeutic regimen. Similarly, the risks of occurrence and recurrence of cancer-associated VTE were found to vary according to the type and spread of the malignant disease [11]. Recent clinical trials assessing DOACs for cancer-associated VTE reported that DOACs seemed to be a reasonable treatment for VTE in such patients [12]. However, it should be noted that in these trials, bleeding events occurred in cases with gastrointestinal and urological tumors; such an occurrence of bleeding events in different types of cancers may also apply to DAPT after PCI in cancer patients. The traditional stratification of risks for bleeding and ischemic events after coronary stent implantation may need to be supplemented with information on the cancer type, progression, and chemotherapeutic regimen.
Regorafenib, an oral multi-targeted receptor tyrosine kinase inhibitor that targets VEGF (thereby affecting cell proliferation and angiogenesis), has been indicated for metastatic colorectal carcinoma. However, it is associated with cardiovascular complications such as hypertension, hemorrhage, thrombosis, and heart failure [2, 10, 13]. Regorafenib was previously reported to be less involved in thrombosis as compared to similar drugs, and has been relatively well-tolerated by patients [13]. However, increased platelet activation, endothelial dysfunction, and dysfunctional nitric oxide metabolism due to VEGF inhibitors result in thrombosis, because VEGF is an important signaling factor for endothelial cell health, which is essential for blood vessel formation and maintenance [10]. Thus, VEGF is important for endothelial cell health and vascular repair in patients undergoing PCI. As a result, VEGF inhibitors, such as regorafenib, might be associated with ST. In our case, it was important to consider a change in the chemotherapeutic regimen before PCI. However, the patient wished to continue regorafenib, because it was an almost final-line treatment for his cancer. Oncology and cardiovascular experts should make every effort to provide optimal medical care while respecting the patients' wishes.
The management of hemodynamically significant CAD in cancer patients, especially those undergoing chemotherapy, has not been fully established. Optimal stent replacement during PCI under intracoronary imaging could reduce the risk of ST, but this may be insufficient. The optimal treatment strategy for cancer patients with CAD, including invasive revascularization, antithrombotic therapy, and chemotherapy, needs to be verified. Future developments in the field of cardio-oncology will need to adapt to changes in the patient population and focus on optimal prevention and surveillance strategies accordingly.
Abbreviations
ATEsarterial thromboembolic events
BNPB-type natriuretic peptide
CADcoronary artery disease
CAGcoronary angiography
DAPTdual-antiplatelet therapy
DESdrug-eluting stent
DOACdirect oral anticoagulant
DVTdeep venous thrombosis
HLhigh-lateral
OFDIoptical frequency domain imaging
IVUSintravascular ultrasound imaging
LADleft anterior descending
PCIpercutaneous coronary intervention
STstent thrombosis
VEGFvascular endothelial growth factor
VTEvenous thromboembolism
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KS and TO managed the patient and wrote and revised the manuscript. KY, KZ and SM revised the manuscript and figures. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and in its additional files.
Ethics approval and consent to participate
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or with comparable ethical standards.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images and videos. A copy of the written consent is available for review by the editor of this journal.
Competing interests
The authors declare that they have no competing interests. | AMLODIPINE BESYLATE, APIXABAN, ASPIRIN, BISOPROLOL, ENALAPRIL, ESOMEPRAZOLE MAGNESIUM, FUROSEMIDE, INSULIN DEGLUDEC, MITIGLINIDE, PRASUGREL HYDROCHLORIDE, REGORAFENIB, SITAGLIPTIN | DrugsGivenReaction | CC BY | 33516171 | 18,873,767 | 2021-01-30 |
What is the weight of the patient? | Early stent thrombosis confirmed in a cancer patient receiving regorafenib, despite triple antithrombotic therapy: a case report.
While developments in oncology have lengthened survival in patients with cancer, such patients often develop cardiovascular diseases. Thus, percutaneous coronary intervention (PCI) is frequently undertaken in them. Although stent thrombosis remains a fatal complication in stent-based PCI, worldwide consensus panels tend to recommend shorter duration of dual-antiplatelet therapy. This is based on its clinical efficacy that has resulted from technological innovation. However, there is insufficient discussion on the risk of stent thrombosis in cancer patients with coronary artery disease, especially in those undergoing chemotherapeutic regimens that have a risk for thrombosis, such as regimens with the anti-vascular endothelial growth factor. Presented here is a case of early stent thrombosis that occurred in a cancer patient on regorafenib, despite the administration of triple antithrombotic therapy. Case presentation A 66-year-old Japanese male patient received regorafenib for metastatic colorectal carcinoma and apixaban for deep vein thrombosis. Coronary angiography revealed severe stenosis in the proximal left anterior descending artery. A sirolimus-eluting stent was implanted, without malapposition and under-expansion, under intravascular ultrasound guidance while administering a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day). However, he was admitted to the hospital for exacerbation of heart failure 1 month after PCI. Coronary angiography revealed contrastive defects in the previous stent. Optical frequency domain imaging confirmed stent thrombosis. PCI was successfully performed with perfusion balloon long-inflation. Antithrombotic therapy was enhanced (aspirin: 100 mg/day, ticagrelor: 120 mg/day, and apixaban: 10 mg/day) and regorafenib was discontinued permanently. While ischemic events did not occur thereafter, the patient died due to metastatic carcinoma progression.
This case suggests that anti-vascular endothelial growth factor might contribute to early stent thrombosis, despite triple antithrombotic therapy. Further discussion is needed on the surveillance and management of cancer patients with coronary artery disease receiving chemotherapy, which carries a risk of thrombosis.
Background
Cardio-oncology is a rapidly growing subspeciality worldwide. Recent oncological developments have led to favorable clinical outcomes in cancer patients; however, many cancer survivors develop cardiovascular diseases. As a result, percutaneous coronary intervention (PCI) is frequently performed in cancer patients, who also develop coronary artery disease (CAD) while receiving chemotherapy.
Stent thrombosis (ST) is a rare but serious complication of PCI. Malignant disease is known as a strong risk factor for the development of ST and hemorrhage after stent implantation [1]. In addition, many modern chemotherapies are associated with vascular complications such as thrombosis and major bleeding [2]. Cancer and its treatment with chemotherapy are associated with a potential risk of thrombotic and bleeding complications in patients undergoing PCI. However, currently, there is insufficient evidence for optimal prevention and risk stratification of ST in these patients.
Described below is a case of early ST that was confirmed by optical frequency domain imaging (OFDI). In this case, ST occurred in a cancer patient receiving anti-vascular endothelial growth factor (VEGF) therapy in our hospital despite the administration of a triple antithrombotic therapy.
Case presentation
A 66-year-old Japanese male patient had received regorafenib (160 mg/day) as an anticancer treatment for metastatic colorectal carcinoma. His medical history included hypertension, diabetes mellitus, dyslipidemia, chronic heart failure, deep vein thrombosis (DVT), and permanent pacemaker implantation due to complete atrioventricular block. His DVT had been managed with low-dose apixaban (5 mg/day; body weight: 75 kg, creatinine: 1.0 mg/dL) to avoid bleeding complications.
Two months ago, he had suffered from non-ST-elevation myocardial infarction with the high-lateral (HL) branch as the culprit lesion, accompanied by chest discomfort; the HL branch occlusion was treated with balloon dilation only to avoid the need of a long-term triple antithrombotic therapy. At the same time, coronary angiography (CAG) revealed severe stenosis in the proximal left anterior descending (LAD) artery. A fractional flow reserve value of 0.72 confirmed a physiologically significant lesion. After PCI for the HL branch, regorafenib was withdrawn temporarily, and a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day) was successfully continued for two months without bleeding complications. Subsequently, the patient underwent PCI for severe stenosis in the LAD lesion two months after PCI for HL, as he demonstrated good tolerance to the triple antithrombotic therapy. Other medications administered included bisoprolol (1.25 mg/day), enalapril (2.5 mg/day), furosemide (20 mg/day), esomeprazole (20 mg/day), amlodipine (5 mg/day), sitagliptin (50 mg/day), mitiglinide (30 mg/day), and insulin degludec (9 units). In addition, routine blood testing revealed an elevated level of B-type natriuretic peptide (BNP), normal kidney function, high value of HbA1c, and mild anemia (BNP: 191.6 pg/mL, creatinine: 0.68 mg/dL, estimated glomerular filtration rate: 89.3 mL/minute/1.73 m2, HbA1c: 8.4%, hemoglobin: 9.9 g/dL, and platelet count: 318 × 103/µL). He was classified as having a high thrombotic and bleeding risk at this time, according to the CREDO-Kyoto thrombotic and bleeding risk scores. A sirolimus-eluting stent, which is a drug-eluting stent (DES) (Ultimaster Tansei 3.5/38 mm; Terumo Corporation, Tokyo, Japan), was implanted in the LAD lesion without malapposition or significant under-expansion, as confirmed by intravascular ultrasound imaging (IVUS) analysis (Fig. 1). After PCI for the LAD, regorafenib was resumed because it exhibited a clinical effect on the patient's cancer. Nevertheless, the patient was admitted to our hospital for congestive heart failure with dyspnea one month later (BNP: 1,512.5 pg/mL). Echocardiography demonstrated new severe hypokinesis of the anteroseptal wall and apex. Despite continued triple antithrombotic therapy, CAG revealed focal and eccentric contrastive defects in the previous LAD stent, and OFDI confirmed ST (Fig. 2a–e). A 3.5/20 mm perfusion balloon (Ryusei, Kaneka Medical, Tokyo, Japan) was inflated for 3 min using an embolic protection device (Fig. 2f). CAG and OFDI confirmed optimal initial gain in the ST site and thrombolysis in myocardial infarction flow grade 3, with no complications including distal emboli (Fig. 2g–k). Antithrombotic therapy was further enhanced temporarily to prevent the recurrence of ST; it included aspirin (100 mg/day), ticagrelor (120 mg/day), and apixaban (10 mg/day). The administration of regorafenib was discontinued after PCI for ST in the LAD, and aspirin and ticagrelor were discontinued 1 and 2 months later, respectively. No further thromboembolic events (including definite/probable ST) were observed, and heart failure was managed well. However, he died due to the progression of metastatic colorectal carcinoma about 3 months after ST onset.Fig. 1 Percutaneous coronary intervention for left anterior descending artery under intravascular ultrasound guidance. a, b Severe stenosis in the left anterior descending (LAD) artery (arrowhead) on initial coronary angiography (CAG). c Stent implantation in the LAD. d–g Final CAG showing an optimal result, with longitudinal and cross-sectional views in intravascular ultrasound imaging; acceptable stent expansion is confirmed
Fig. 2 Early stent thrombosis and revascularization. a Focal and eccentric contrastive defect in the previous left anterior descending stent. b–e Cross-sectional and longitudinal views of the stent thrombosis in optical frequency domain imaging (OFDI). f 3.5-mm perfusion balloon is dilated for 3 min. g Final coronary angiography reveals reduction of the contrastive defect and thrombolysis in myocardial infarction flow grade 3 without distal emboli. h–k Cross-sectional and longitudinal views in OFDI showing an increase in the lumen area and a small amount of residual thrombus
Discussion and conclusions
In this modern stent-based PCI era, ST represents a fatal and life-threatening complication. According to previous reports, the risk of ST is strongly associated with both, the patient background and procedural aspects [1, 3]. Certain patient background factors are independent predictors of a bleeding risk; malignant disease is a strong risk factor for major bleeding after PCI, as well as ST [1]. Our patient was classified as having a high thrombotic (4 points: anemia, heart failure, diabetes mellitus) and bleeding (4 points: heart failure, prior myocardial infarction, malignancy) risk, according to the CREDO-Kyoto thrombotic and bleeding risk scores [3]. Thus, we always had to consider the tradeoffs between the thrombotic and bleeding risks and PCI while caring for him.
The most frequent optical coherence tomography findings in early ST (within 30 days after index PCI) are uncovered struts and under-expansion [4]. Incomplete neointimal coverage of the struts in the early phase is normal, but the risk of ST associated with this procedure needs to be minimized. This risk could be reduced by optimizing stent placement with intracoronary imaging techniques and developing newer DES technology [1]. Moreover, dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor blocker after coronary stent implantation has been effective in preventing ST, and has been the standard treatment. Regarding P2Y12 receptor blockers, prasugrel or ticagrelor, in combination with aspirin, has been associated with a greater reduction in ST as compared to a combination of clopidogrel and aspirin [5, 6]. Furthermore, among stented patients with acute coronary syndrome treated by DAPT, low-dose rivaroxaban administration has been associated with a reduction in ST [7]. Thus, antithrombotic therapy after PCI has been established worldwide, but the optimal duration of DAPT remains controversial. Recent global guidelines recommend a shorter duration of DAPT for clinical efficacy. Additionally, it is recommended that the duration of the combination of triple antithrombotic therapy with DAPT and oral anticoagulants be as brief as possible [8]. However, there remains a lack of discussion regarding an appropriate antiplatelet therapy after PCI for cancer patients who are or are not undergoing chemotherapy. In our patient, although new-generation DES implantation was optimized by IVUS and a more potent antithrombotic therapy (DAPT and direct oral anticoagulant [DOAC]) was continued, early ST still occurred. This suggests that a standardized antithrombotic drug reduction may cause life-threatening ST in cancer patients receiving chemotherapy. The patient in our case was managed by changing the P2Y12 receptor blocker, increasing the DOAC dose, and withdrawing regorafenib until an adequate neointimal coverage of the struts was achieved. Thus, the risk of ST and the optimal duration of DAPT in cancer patients undergoing chemotherapy should be explored further.
While the association between venous thromboembolism (VTE) and malignancy is well-discussed, arterial thrombosis has more recently been recognized as a serious complication of cancer and chemotherapy. One study, based on a large database in the USA, reported that the incidence of arterial thromboembolic events (ATEs) in patients with cancer at 6 months was 4.7% [9]; patients with lung, gastric, or pancreatic cancers had the highest rates of ATEs (8.3, 6.5, and 5.9%, respectively). Moreover, an advanced stage of cancer was associated with a significant increase in the incidence of ATEs (stage 0 vs. stage 4: 2.3% vs. 7.7% at 6 months). Furthermore, certain chemotherapeutic agents, including VEGF inhibitors, have been reported to be associated with ATEs [10]; cisplatin, nilotinib, ponatinib, 5-FU, and capecitabine are particularly associated with a high incidence of coronary artery thrombotic events. Thus, while determining the risk of ischemic events after PCI, physicians should take into account the type of cancer, progression, and chemotherapeutic regimen. Similarly, the risks of occurrence and recurrence of cancer-associated VTE were found to vary according to the type and spread of the malignant disease [11]. Recent clinical trials assessing DOACs for cancer-associated VTE reported that DOACs seemed to be a reasonable treatment for VTE in such patients [12]. However, it should be noted that in these trials, bleeding events occurred in cases with gastrointestinal and urological tumors; such an occurrence of bleeding events in different types of cancers may also apply to DAPT after PCI in cancer patients. The traditional stratification of risks for bleeding and ischemic events after coronary stent implantation may need to be supplemented with information on the cancer type, progression, and chemotherapeutic regimen.
Regorafenib, an oral multi-targeted receptor tyrosine kinase inhibitor that targets VEGF (thereby affecting cell proliferation and angiogenesis), has been indicated for metastatic colorectal carcinoma. However, it is associated with cardiovascular complications such as hypertension, hemorrhage, thrombosis, and heart failure [2, 10, 13]. Regorafenib was previously reported to be less involved in thrombosis as compared to similar drugs, and has been relatively well-tolerated by patients [13]. However, increased platelet activation, endothelial dysfunction, and dysfunctional nitric oxide metabolism due to VEGF inhibitors result in thrombosis, because VEGF is an important signaling factor for endothelial cell health, which is essential for blood vessel formation and maintenance [10]. Thus, VEGF is important for endothelial cell health and vascular repair in patients undergoing PCI. As a result, VEGF inhibitors, such as regorafenib, might be associated with ST. In our case, it was important to consider a change in the chemotherapeutic regimen before PCI. However, the patient wished to continue regorafenib, because it was an almost final-line treatment for his cancer. Oncology and cardiovascular experts should make every effort to provide optimal medical care while respecting the patients' wishes.
The management of hemodynamically significant CAD in cancer patients, especially those undergoing chemotherapy, has not been fully established. Optimal stent replacement during PCI under intracoronary imaging could reduce the risk of ST, but this may be insufficient. The optimal treatment strategy for cancer patients with CAD, including invasive revascularization, antithrombotic therapy, and chemotherapy, needs to be verified. Future developments in the field of cardio-oncology will need to adapt to changes in the patient population and focus on optimal prevention and surveillance strategies accordingly.
Abbreviations
ATEsarterial thromboembolic events
BNPB-type natriuretic peptide
CADcoronary artery disease
CAGcoronary angiography
DAPTdual-antiplatelet therapy
DESdrug-eluting stent
DOACdirect oral anticoagulant
DVTdeep venous thrombosis
HLhigh-lateral
OFDIoptical frequency domain imaging
IVUSintravascular ultrasound imaging
LADleft anterior descending
PCIpercutaneous coronary intervention
STstent thrombosis
VEGFvascular endothelial growth factor
VTEvenous thromboembolism
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KS and TO managed the patient and wrote and revised the manuscript. KY, KZ and SM revised the manuscript and figures. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and in its additional files.
Ethics approval and consent to participate
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or with comparable ethical standards.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images and videos. A copy of the written consent is available for review by the editor of this journal.
Competing interests
The authors declare that they have no competing interests. | 75 kg. | Weight | CC BY | 33516171 | 18,873,767 | 2021-01-30 |
What was the dosage of drug 'INSULIN DEGLUDEC'? | Early stent thrombosis confirmed in a cancer patient receiving regorafenib, despite triple antithrombotic therapy: a case report.
While developments in oncology have lengthened survival in patients with cancer, such patients often develop cardiovascular diseases. Thus, percutaneous coronary intervention (PCI) is frequently undertaken in them. Although stent thrombosis remains a fatal complication in stent-based PCI, worldwide consensus panels tend to recommend shorter duration of dual-antiplatelet therapy. This is based on its clinical efficacy that has resulted from technological innovation. However, there is insufficient discussion on the risk of stent thrombosis in cancer patients with coronary artery disease, especially in those undergoing chemotherapeutic regimens that have a risk for thrombosis, such as regimens with the anti-vascular endothelial growth factor. Presented here is a case of early stent thrombosis that occurred in a cancer patient on regorafenib, despite the administration of triple antithrombotic therapy. Case presentation A 66-year-old Japanese male patient received regorafenib for metastatic colorectal carcinoma and apixaban for deep vein thrombosis. Coronary angiography revealed severe stenosis in the proximal left anterior descending artery. A sirolimus-eluting stent was implanted, without malapposition and under-expansion, under intravascular ultrasound guidance while administering a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day). However, he was admitted to the hospital for exacerbation of heart failure 1 month after PCI. Coronary angiography revealed contrastive defects in the previous stent. Optical frequency domain imaging confirmed stent thrombosis. PCI was successfully performed with perfusion balloon long-inflation. Antithrombotic therapy was enhanced (aspirin: 100 mg/day, ticagrelor: 120 mg/day, and apixaban: 10 mg/day) and regorafenib was discontinued permanently. While ischemic events did not occur thereafter, the patient died due to metastatic carcinoma progression.
This case suggests that anti-vascular endothelial growth factor might contribute to early stent thrombosis, despite triple antithrombotic therapy. Further discussion is needed on the surveillance and management of cancer patients with coronary artery disease receiving chemotherapy, which carries a risk of thrombosis.
Background
Cardio-oncology is a rapidly growing subspeciality worldwide. Recent oncological developments have led to favorable clinical outcomes in cancer patients; however, many cancer survivors develop cardiovascular diseases. As a result, percutaneous coronary intervention (PCI) is frequently performed in cancer patients, who also develop coronary artery disease (CAD) while receiving chemotherapy.
Stent thrombosis (ST) is a rare but serious complication of PCI. Malignant disease is known as a strong risk factor for the development of ST and hemorrhage after stent implantation [1]. In addition, many modern chemotherapies are associated with vascular complications such as thrombosis and major bleeding [2]. Cancer and its treatment with chemotherapy are associated with a potential risk of thrombotic and bleeding complications in patients undergoing PCI. However, currently, there is insufficient evidence for optimal prevention and risk stratification of ST in these patients.
Described below is a case of early ST that was confirmed by optical frequency domain imaging (OFDI). In this case, ST occurred in a cancer patient receiving anti-vascular endothelial growth factor (VEGF) therapy in our hospital despite the administration of a triple antithrombotic therapy.
Case presentation
A 66-year-old Japanese male patient had received regorafenib (160 mg/day) as an anticancer treatment for metastatic colorectal carcinoma. His medical history included hypertension, diabetes mellitus, dyslipidemia, chronic heart failure, deep vein thrombosis (DVT), and permanent pacemaker implantation due to complete atrioventricular block. His DVT had been managed with low-dose apixaban (5 mg/day; body weight: 75 kg, creatinine: 1.0 mg/dL) to avoid bleeding complications.
Two months ago, he had suffered from non-ST-elevation myocardial infarction with the high-lateral (HL) branch as the culprit lesion, accompanied by chest discomfort; the HL branch occlusion was treated with balloon dilation only to avoid the need of a long-term triple antithrombotic therapy. At the same time, coronary angiography (CAG) revealed severe stenosis in the proximal left anterior descending (LAD) artery. A fractional flow reserve value of 0.72 confirmed a physiologically significant lesion. After PCI for the HL branch, regorafenib was withdrawn temporarily, and a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day) was successfully continued for two months without bleeding complications. Subsequently, the patient underwent PCI for severe stenosis in the LAD lesion two months after PCI for HL, as he demonstrated good tolerance to the triple antithrombotic therapy. Other medications administered included bisoprolol (1.25 mg/day), enalapril (2.5 mg/day), furosemide (20 mg/day), esomeprazole (20 mg/day), amlodipine (5 mg/day), sitagliptin (50 mg/day), mitiglinide (30 mg/day), and insulin degludec (9 units). In addition, routine blood testing revealed an elevated level of B-type natriuretic peptide (BNP), normal kidney function, high value of HbA1c, and mild anemia (BNP: 191.6 pg/mL, creatinine: 0.68 mg/dL, estimated glomerular filtration rate: 89.3 mL/minute/1.73 m2, HbA1c: 8.4%, hemoglobin: 9.9 g/dL, and platelet count: 318 × 103/µL). He was classified as having a high thrombotic and bleeding risk at this time, according to the CREDO-Kyoto thrombotic and bleeding risk scores. A sirolimus-eluting stent, which is a drug-eluting stent (DES) (Ultimaster Tansei 3.5/38 mm; Terumo Corporation, Tokyo, Japan), was implanted in the LAD lesion without malapposition or significant under-expansion, as confirmed by intravascular ultrasound imaging (IVUS) analysis (Fig. 1). After PCI for the LAD, regorafenib was resumed because it exhibited a clinical effect on the patient's cancer. Nevertheless, the patient was admitted to our hospital for congestive heart failure with dyspnea one month later (BNP: 1,512.5 pg/mL). Echocardiography demonstrated new severe hypokinesis of the anteroseptal wall and apex. Despite continued triple antithrombotic therapy, CAG revealed focal and eccentric contrastive defects in the previous LAD stent, and OFDI confirmed ST (Fig. 2a–e). A 3.5/20 mm perfusion balloon (Ryusei, Kaneka Medical, Tokyo, Japan) was inflated for 3 min using an embolic protection device (Fig. 2f). CAG and OFDI confirmed optimal initial gain in the ST site and thrombolysis in myocardial infarction flow grade 3, with no complications including distal emboli (Fig. 2g–k). Antithrombotic therapy was further enhanced temporarily to prevent the recurrence of ST; it included aspirin (100 mg/day), ticagrelor (120 mg/day), and apixaban (10 mg/day). The administration of regorafenib was discontinued after PCI for ST in the LAD, and aspirin and ticagrelor were discontinued 1 and 2 months later, respectively. No further thromboembolic events (including definite/probable ST) were observed, and heart failure was managed well. However, he died due to the progression of metastatic colorectal carcinoma about 3 months after ST onset.Fig. 1 Percutaneous coronary intervention for left anterior descending artery under intravascular ultrasound guidance. a, b Severe stenosis in the left anterior descending (LAD) artery (arrowhead) on initial coronary angiography (CAG). c Stent implantation in the LAD. d–g Final CAG showing an optimal result, with longitudinal and cross-sectional views in intravascular ultrasound imaging; acceptable stent expansion is confirmed
Fig. 2 Early stent thrombosis and revascularization. a Focal and eccentric contrastive defect in the previous left anterior descending stent. b–e Cross-sectional and longitudinal views of the stent thrombosis in optical frequency domain imaging (OFDI). f 3.5-mm perfusion balloon is dilated for 3 min. g Final coronary angiography reveals reduction of the contrastive defect and thrombolysis in myocardial infarction flow grade 3 without distal emboli. h–k Cross-sectional and longitudinal views in OFDI showing an increase in the lumen area and a small amount of residual thrombus
Discussion and conclusions
In this modern stent-based PCI era, ST represents a fatal and life-threatening complication. According to previous reports, the risk of ST is strongly associated with both, the patient background and procedural aspects [1, 3]. Certain patient background factors are independent predictors of a bleeding risk; malignant disease is a strong risk factor for major bleeding after PCI, as well as ST [1]. Our patient was classified as having a high thrombotic (4 points: anemia, heart failure, diabetes mellitus) and bleeding (4 points: heart failure, prior myocardial infarction, malignancy) risk, according to the CREDO-Kyoto thrombotic and bleeding risk scores [3]. Thus, we always had to consider the tradeoffs between the thrombotic and bleeding risks and PCI while caring for him.
The most frequent optical coherence tomography findings in early ST (within 30 days after index PCI) are uncovered struts and under-expansion [4]. Incomplete neointimal coverage of the struts in the early phase is normal, but the risk of ST associated with this procedure needs to be minimized. This risk could be reduced by optimizing stent placement with intracoronary imaging techniques and developing newer DES technology [1]. Moreover, dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor blocker after coronary stent implantation has been effective in preventing ST, and has been the standard treatment. Regarding P2Y12 receptor blockers, prasugrel or ticagrelor, in combination with aspirin, has been associated with a greater reduction in ST as compared to a combination of clopidogrel and aspirin [5, 6]. Furthermore, among stented patients with acute coronary syndrome treated by DAPT, low-dose rivaroxaban administration has been associated with a reduction in ST [7]. Thus, antithrombotic therapy after PCI has been established worldwide, but the optimal duration of DAPT remains controversial. Recent global guidelines recommend a shorter duration of DAPT for clinical efficacy. Additionally, it is recommended that the duration of the combination of triple antithrombotic therapy with DAPT and oral anticoagulants be as brief as possible [8]. However, there remains a lack of discussion regarding an appropriate antiplatelet therapy after PCI for cancer patients who are or are not undergoing chemotherapy. In our patient, although new-generation DES implantation was optimized by IVUS and a more potent antithrombotic therapy (DAPT and direct oral anticoagulant [DOAC]) was continued, early ST still occurred. This suggests that a standardized antithrombotic drug reduction may cause life-threatening ST in cancer patients receiving chemotherapy. The patient in our case was managed by changing the P2Y12 receptor blocker, increasing the DOAC dose, and withdrawing regorafenib until an adequate neointimal coverage of the struts was achieved. Thus, the risk of ST and the optimal duration of DAPT in cancer patients undergoing chemotherapy should be explored further.
While the association between venous thromboembolism (VTE) and malignancy is well-discussed, arterial thrombosis has more recently been recognized as a serious complication of cancer and chemotherapy. One study, based on a large database in the USA, reported that the incidence of arterial thromboembolic events (ATEs) in patients with cancer at 6 months was 4.7% [9]; patients with lung, gastric, or pancreatic cancers had the highest rates of ATEs (8.3, 6.5, and 5.9%, respectively). Moreover, an advanced stage of cancer was associated with a significant increase in the incidence of ATEs (stage 0 vs. stage 4: 2.3% vs. 7.7% at 6 months). Furthermore, certain chemotherapeutic agents, including VEGF inhibitors, have been reported to be associated with ATEs [10]; cisplatin, nilotinib, ponatinib, 5-FU, and capecitabine are particularly associated with a high incidence of coronary artery thrombotic events. Thus, while determining the risk of ischemic events after PCI, physicians should take into account the type of cancer, progression, and chemotherapeutic regimen. Similarly, the risks of occurrence and recurrence of cancer-associated VTE were found to vary according to the type and spread of the malignant disease [11]. Recent clinical trials assessing DOACs for cancer-associated VTE reported that DOACs seemed to be a reasonable treatment for VTE in such patients [12]. However, it should be noted that in these trials, bleeding events occurred in cases with gastrointestinal and urological tumors; such an occurrence of bleeding events in different types of cancers may also apply to DAPT after PCI in cancer patients. The traditional stratification of risks for bleeding and ischemic events after coronary stent implantation may need to be supplemented with information on the cancer type, progression, and chemotherapeutic regimen.
Regorafenib, an oral multi-targeted receptor tyrosine kinase inhibitor that targets VEGF (thereby affecting cell proliferation and angiogenesis), has been indicated for metastatic colorectal carcinoma. However, it is associated with cardiovascular complications such as hypertension, hemorrhage, thrombosis, and heart failure [2, 10, 13]. Regorafenib was previously reported to be less involved in thrombosis as compared to similar drugs, and has been relatively well-tolerated by patients [13]. However, increased platelet activation, endothelial dysfunction, and dysfunctional nitric oxide metabolism due to VEGF inhibitors result in thrombosis, because VEGF is an important signaling factor for endothelial cell health, which is essential for blood vessel formation and maintenance [10]. Thus, VEGF is important for endothelial cell health and vascular repair in patients undergoing PCI. As a result, VEGF inhibitors, such as regorafenib, might be associated with ST. In our case, it was important to consider a change in the chemotherapeutic regimen before PCI. However, the patient wished to continue regorafenib, because it was an almost final-line treatment for his cancer. Oncology and cardiovascular experts should make every effort to provide optimal medical care while respecting the patients' wishes.
The management of hemodynamically significant CAD in cancer patients, especially those undergoing chemotherapy, has not been fully established. Optimal stent replacement during PCI under intracoronary imaging could reduce the risk of ST, but this may be insufficient. The optimal treatment strategy for cancer patients with CAD, including invasive revascularization, antithrombotic therapy, and chemotherapy, needs to be verified. Future developments in the field of cardio-oncology will need to adapt to changes in the patient population and focus on optimal prevention and surveillance strategies accordingly.
Abbreviations
ATEsarterial thromboembolic events
BNPB-type natriuretic peptide
CADcoronary artery disease
CAGcoronary angiography
DAPTdual-antiplatelet therapy
DESdrug-eluting stent
DOACdirect oral anticoagulant
DVTdeep venous thrombosis
HLhigh-lateral
OFDIoptical frequency domain imaging
IVUSintravascular ultrasound imaging
LADleft anterior descending
PCIpercutaneous coronary intervention
STstent thrombosis
VEGFvascular endothelial growth factor
VTEvenous thromboembolism
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KS and TO managed the patient and wrote and revised the manuscript. KY, KZ and SM revised the manuscript and figures. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and in its additional files.
Ethics approval and consent to participate
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or with comparable ethical standards.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images and videos. A copy of the written consent is available for review by the editor of this journal.
Competing interests
The authors declare that they have no competing interests. | 9 UNITS | DrugDosageText | CC BY | 33516171 | 18,873,767 | 2021-01-30 |
What was the outcome of reaction 'Cardiac failure'? | Early stent thrombosis confirmed in a cancer patient receiving regorafenib, despite triple antithrombotic therapy: a case report.
While developments in oncology have lengthened survival in patients with cancer, such patients often develop cardiovascular diseases. Thus, percutaneous coronary intervention (PCI) is frequently undertaken in them. Although stent thrombosis remains a fatal complication in stent-based PCI, worldwide consensus panels tend to recommend shorter duration of dual-antiplatelet therapy. This is based on its clinical efficacy that has resulted from technological innovation. However, there is insufficient discussion on the risk of stent thrombosis in cancer patients with coronary artery disease, especially in those undergoing chemotherapeutic regimens that have a risk for thrombosis, such as regimens with the anti-vascular endothelial growth factor. Presented here is a case of early stent thrombosis that occurred in a cancer patient on regorafenib, despite the administration of triple antithrombotic therapy. Case presentation A 66-year-old Japanese male patient received regorafenib for metastatic colorectal carcinoma and apixaban for deep vein thrombosis. Coronary angiography revealed severe stenosis in the proximal left anterior descending artery. A sirolimus-eluting stent was implanted, without malapposition and under-expansion, under intravascular ultrasound guidance while administering a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day). However, he was admitted to the hospital for exacerbation of heart failure 1 month after PCI. Coronary angiography revealed contrastive defects in the previous stent. Optical frequency domain imaging confirmed stent thrombosis. PCI was successfully performed with perfusion balloon long-inflation. Antithrombotic therapy was enhanced (aspirin: 100 mg/day, ticagrelor: 120 mg/day, and apixaban: 10 mg/day) and regorafenib was discontinued permanently. While ischemic events did not occur thereafter, the patient died due to metastatic carcinoma progression.
This case suggests that anti-vascular endothelial growth factor might contribute to early stent thrombosis, despite triple antithrombotic therapy. Further discussion is needed on the surveillance and management of cancer patients with coronary artery disease receiving chemotherapy, which carries a risk of thrombosis.
Background
Cardio-oncology is a rapidly growing subspeciality worldwide. Recent oncological developments have led to favorable clinical outcomes in cancer patients; however, many cancer survivors develop cardiovascular diseases. As a result, percutaneous coronary intervention (PCI) is frequently performed in cancer patients, who also develop coronary artery disease (CAD) while receiving chemotherapy.
Stent thrombosis (ST) is a rare but serious complication of PCI. Malignant disease is known as a strong risk factor for the development of ST and hemorrhage after stent implantation [1]. In addition, many modern chemotherapies are associated with vascular complications such as thrombosis and major bleeding [2]. Cancer and its treatment with chemotherapy are associated with a potential risk of thrombotic and bleeding complications in patients undergoing PCI. However, currently, there is insufficient evidence for optimal prevention and risk stratification of ST in these patients.
Described below is a case of early ST that was confirmed by optical frequency domain imaging (OFDI). In this case, ST occurred in a cancer patient receiving anti-vascular endothelial growth factor (VEGF) therapy in our hospital despite the administration of a triple antithrombotic therapy.
Case presentation
A 66-year-old Japanese male patient had received regorafenib (160 mg/day) as an anticancer treatment for metastatic colorectal carcinoma. His medical history included hypertension, diabetes mellitus, dyslipidemia, chronic heart failure, deep vein thrombosis (DVT), and permanent pacemaker implantation due to complete atrioventricular block. His DVT had been managed with low-dose apixaban (5 mg/day; body weight: 75 kg, creatinine: 1.0 mg/dL) to avoid bleeding complications.
Two months ago, he had suffered from non-ST-elevation myocardial infarction with the high-lateral (HL) branch as the culprit lesion, accompanied by chest discomfort; the HL branch occlusion was treated with balloon dilation only to avoid the need of a long-term triple antithrombotic therapy. At the same time, coronary angiography (CAG) revealed severe stenosis in the proximal left anterior descending (LAD) artery. A fractional flow reserve value of 0.72 confirmed a physiologically significant lesion. After PCI for the HL branch, regorafenib was withdrawn temporarily, and a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day) was successfully continued for two months without bleeding complications. Subsequently, the patient underwent PCI for severe stenosis in the LAD lesion two months after PCI for HL, as he demonstrated good tolerance to the triple antithrombotic therapy. Other medications administered included bisoprolol (1.25 mg/day), enalapril (2.5 mg/day), furosemide (20 mg/day), esomeprazole (20 mg/day), amlodipine (5 mg/day), sitagliptin (50 mg/day), mitiglinide (30 mg/day), and insulin degludec (9 units). In addition, routine blood testing revealed an elevated level of B-type natriuretic peptide (BNP), normal kidney function, high value of HbA1c, and mild anemia (BNP: 191.6 pg/mL, creatinine: 0.68 mg/dL, estimated glomerular filtration rate: 89.3 mL/minute/1.73 m2, HbA1c: 8.4%, hemoglobin: 9.9 g/dL, and platelet count: 318 × 103/µL). He was classified as having a high thrombotic and bleeding risk at this time, according to the CREDO-Kyoto thrombotic and bleeding risk scores. A sirolimus-eluting stent, which is a drug-eluting stent (DES) (Ultimaster Tansei 3.5/38 mm; Terumo Corporation, Tokyo, Japan), was implanted in the LAD lesion without malapposition or significant under-expansion, as confirmed by intravascular ultrasound imaging (IVUS) analysis (Fig. 1). After PCI for the LAD, regorafenib was resumed because it exhibited a clinical effect on the patient's cancer. Nevertheless, the patient was admitted to our hospital for congestive heart failure with dyspnea one month later (BNP: 1,512.5 pg/mL). Echocardiography demonstrated new severe hypokinesis of the anteroseptal wall and apex. Despite continued triple antithrombotic therapy, CAG revealed focal and eccentric contrastive defects in the previous LAD stent, and OFDI confirmed ST (Fig. 2a–e). A 3.5/20 mm perfusion balloon (Ryusei, Kaneka Medical, Tokyo, Japan) was inflated for 3 min using an embolic protection device (Fig. 2f). CAG and OFDI confirmed optimal initial gain in the ST site and thrombolysis in myocardial infarction flow grade 3, with no complications including distal emboli (Fig. 2g–k). Antithrombotic therapy was further enhanced temporarily to prevent the recurrence of ST; it included aspirin (100 mg/day), ticagrelor (120 mg/day), and apixaban (10 mg/day). The administration of regorafenib was discontinued after PCI for ST in the LAD, and aspirin and ticagrelor were discontinued 1 and 2 months later, respectively. No further thromboembolic events (including definite/probable ST) were observed, and heart failure was managed well. However, he died due to the progression of metastatic colorectal carcinoma about 3 months after ST onset.Fig. 1 Percutaneous coronary intervention for left anterior descending artery under intravascular ultrasound guidance. a, b Severe stenosis in the left anterior descending (LAD) artery (arrowhead) on initial coronary angiography (CAG). c Stent implantation in the LAD. d–g Final CAG showing an optimal result, with longitudinal and cross-sectional views in intravascular ultrasound imaging; acceptable stent expansion is confirmed
Fig. 2 Early stent thrombosis and revascularization. a Focal and eccentric contrastive defect in the previous left anterior descending stent. b–e Cross-sectional and longitudinal views of the stent thrombosis in optical frequency domain imaging (OFDI). f 3.5-mm perfusion balloon is dilated for 3 min. g Final coronary angiography reveals reduction of the contrastive defect and thrombolysis in myocardial infarction flow grade 3 without distal emboli. h–k Cross-sectional and longitudinal views in OFDI showing an increase in the lumen area and a small amount of residual thrombus
Discussion and conclusions
In this modern stent-based PCI era, ST represents a fatal and life-threatening complication. According to previous reports, the risk of ST is strongly associated with both, the patient background and procedural aspects [1, 3]. Certain patient background factors are independent predictors of a bleeding risk; malignant disease is a strong risk factor for major bleeding after PCI, as well as ST [1]. Our patient was classified as having a high thrombotic (4 points: anemia, heart failure, diabetes mellitus) and bleeding (4 points: heart failure, prior myocardial infarction, malignancy) risk, according to the CREDO-Kyoto thrombotic and bleeding risk scores [3]. Thus, we always had to consider the tradeoffs between the thrombotic and bleeding risks and PCI while caring for him.
The most frequent optical coherence tomography findings in early ST (within 30 days after index PCI) are uncovered struts and under-expansion [4]. Incomplete neointimal coverage of the struts in the early phase is normal, but the risk of ST associated with this procedure needs to be minimized. This risk could be reduced by optimizing stent placement with intracoronary imaging techniques and developing newer DES technology [1]. Moreover, dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor blocker after coronary stent implantation has been effective in preventing ST, and has been the standard treatment. Regarding P2Y12 receptor blockers, prasugrel or ticagrelor, in combination with aspirin, has been associated with a greater reduction in ST as compared to a combination of clopidogrel and aspirin [5, 6]. Furthermore, among stented patients with acute coronary syndrome treated by DAPT, low-dose rivaroxaban administration has been associated with a reduction in ST [7]. Thus, antithrombotic therapy after PCI has been established worldwide, but the optimal duration of DAPT remains controversial. Recent global guidelines recommend a shorter duration of DAPT for clinical efficacy. Additionally, it is recommended that the duration of the combination of triple antithrombotic therapy with DAPT and oral anticoagulants be as brief as possible [8]. However, there remains a lack of discussion regarding an appropriate antiplatelet therapy after PCI for cancer patients who are or are not undergoing chemotherapy. In our patient, although new-generation DES implantation was optimized by IVUS and a more potent antithrombotic therapy (DAPT and direct oral anticoagulant [DOAC]) was continued, early ST still occurred. This suggests that a standardized antithrombotic drug reduction may cause life-threatening ST in cancer patients receiving chemotherapy. The patient in our case was managed by changing the P2Y12 receptor blocker, increasing the DOAC dose, and withdrawing regorafenib until an adequate neointimal coverage of the struts was achieved. Thus, the risk of ST and the optimal duration of DAPT in cancer patients undergoing chemotherapy should be explored further.
While the association between venous thromboembolism (VTE) and malignancy is well-discussed, arterial thrombosis has more recently been recognized as a serious complication of cancer and chemotherapy. One study, based on a large database in the USA, reported that the incidence of arterial thromboembolic events (ATEs) in patients with cancer at 6 months was 4.7% [9]; patients with lung, gastric, or pancreatic cancers had the highest rates of ATEs (8.3, 6.5, and 5.9%, respectively). Moreover, an advanced stage of cancer was associated with a significant increase in the incidence of ATEs (stage 0 vs. stage 4: 2.3% vs. 7.7% at 6 months). Furthermore, certain chemotherapeutic agents, including VEGF inhibitors, have been reported to be associated with ATEs [10]; cisplatin, nilotinib, ponatinib, 5-FU, and capecitabine are particularly associated with a high incidence of coronary artery thrombotic events. Thus, while determining the risk of ischemic events after PCI, physicians should take into account the type of cancer, progression, and chemotherapeutic regimen. Similarly, the risks of occurrence and recurrence of cancer-associated VTE were found to vary according to the type and spread of the malignant disease [11]. Recent clinical trials assessing DOACs for cancer-associated VTE reported that DOACs seemed to be a reasonable treatment for VTE in such patients [12]. However, it should be noted that in these trials, bleeding events occurred in cases with gastrointestinal and urological tumors; such an occurrence of bleeding events in different types of cancers may also apply to DAPT after PCI in cancer patients. The traditional stratification of risks for bleeding and ischemic events after coronary stent implantation may need to be supplemented with information on the cancer type, progression, and chemotherapeutic regimen.
Regorafenib, an oral multi-targeted receptor tyrosine kinase inhibitor that targets VEGF (thereby affecting cell proliferation and angiogenesis), has been indicated for metastatic colorectal carcinoma. However, it is associated with cardiovascular complications such as hypertension, hemorrhage, thrombosis, and heart failure [2, 10, 13]. Regorafenib was previously reported to be less involved in thrombosis as compared to similar drugs, and has been relatively well-tolerated by patients [13]. However, increased platelet activation, endothelial dysfunction, and dysfunctional nitric oxide metabolism due to VEGF inhibitors result in thrombosis, because VEGF is an important signaling factor for endothelial cell health, which is essential for blood vessel formation and maintenance [10]. Thus, VEGF is important for endothelial cell health and vascular repair in patients undergoing PCI. As a result, VEGF inhibitors, such as regorafenib, might be associated with ST. In our case, it was important to consider a change in the chemotherapeutic regimen before PCI. However, the patient wished to continue regorafenib, because it was an almost final-line treatment for his cancer. Oncology and cardiovascular experts should make every effort to provide optimal medical care while respecting the patients' wishes.
The management of hemodynamically significant CAD in cancer patients, especially those undergoing chemotherapy, has not been fully established. Optimal stent replacement during PCI under intracoronary imaging could reduce the risk of ST, but this may be insufficient. The optimal treatment strategy for cancer patients with CAD, including invasive revascularization, antithrombotic therapy, and chemotherapy, needs to be verified. Future developments in the field of cardio-oncology will need to adapt to changes in the patient population and focus on optimal prevention and surveillance strategies accordingly.
Abbreviations
ATEsarterial thromboembolic events
BNPB-type natriuretic peptide
CADcoronary artery disease
CAGcoronary angiography
DAPTdual-antiplatelet therapy
DESdrug-eluting stent
DOACdirect oral anticoagulant
DVTdeep venous thrombosis
HLhigh-lateral
OFDIoptical frequency domain imaging
IVUSintravascular ultrasound imaging
LADleft anterior descending
PCIpercutaneous coronary intervention
STstent thrombosis
VEGFvascular endothelial growth factor
VTEvenous thromboembolism
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KS and TO managed the patient and wrote and revised the manuscript. KY, KZ and SM revised the manuscript and figures. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and in its additional files.
Ethics approval and consent to participate
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or with comparable ethical standards.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images and videos. A copy of the written consent is available for review by the editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33516171 | 18,873,767 | 2021-01-30 |
What was the outcome of reaction 'Colorectal cancer'? | Early stent thrombosis confirmed in a cancer patient receiving regorafenib, despite triple antithrombotic therapy: a case report.
While developments in oncology have lengthened survival in patients with cancer, such patients often develop cardiovascular diseases. Thus, percutaneous coronary intervention (PCI) is frequently undertaken in them. Although stent thrombosis remains a fatal complication in stent-based PCI, worldwide consensus panels tend to recommend shorter duration of dual-antiplatelet therapy. This is based on its clinical efficacy that has resulted from technological innovation. However, there is insufficient discussion on the risk of stent thrombosis in cancer patients with coronary artery disease, especially in those undergoing chemotherapeutic regimens that have a risk for thrombosis, such as regimens with the anti-vascular endothelial growth factor. Presented here is a case of early stent thrombosis that occurred in a cancer patient on regorafenib, despite the administration of triple antithrombotic therapy. Case presentation A 66-year-old Japanese male patient received regorafenib for metastatic colorectal carcinoma and apixaban for deep vein thrombosis. Coronary angiography revealed severe stenosis in the proximal left anterior descending artery. A sirolimus-eluting stent was implanted, without malapposition and under-expansion, under intravascular ultrasound guidance while administering a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day). However, he was admitted to the hospital for exacerbation of heart failure 1 month after PCI. Coronary angiography revealed contrastive defects in the previous stent. Optical frequency domain imaging confirmed stent thrombosis. PCI was successfully performed with perfusion balloon long-inflation. Antithrombotic therapy was enhanced (aspirin: 100 mg/day, ticagrelor: 120 mg/day, and apixaban: 10 mg/day) and regorafenib was discontinued permanently. While ischemic events did not occur thereafter, the patient died due to metastatic carcinoma progression.
This case suggests that anti-vascular endothelial growth factor might contribute to early stent thrombosis, despite triple antithrombotic therapy. Further discussion is needed on the surveillance and management of cancer patients with coronary artery disease receiving chemotherapy, which carries a risk of thrombosis.
Background
Cardio-oncology is a rapidly growing subspeciality worldwide. Recent oncological developments have led to favorable clinical outcomes in cancer patients; however, many cancer survivors develop cardiovascular diseases. As a result, percutaneous coronary intervention (PCI) is frequently performed in cancer patients, who also develop coronary artery disease (CAD) while receiving chemotherapy.
Stent thrombosis (ST) is a rare but serious complication of PCI. Malignant disease is known as a strong risk factor for the development of ST and hemorrhage after stent implantation [1]. In addition, many modern chemotherapies are associated with vascular complications such as thrombosis and major bleeding [2]. Cancer and its treatment with chemotherapy are associated with a potential risk of thrombotic and bleeding complications in patients undergoing PCI. However, currently, there is insufficient evidence for optimal prevention and risk stratification of ST in these patients.
Described below is a case of early ST that was confirmed by optical frequency domain imaging (OFDI). In this case, ST occurred in a cancer patient receiving anti-vascular endothelial growth factor (VEGF) therapy in our hospital despite the administration of a triple antithrombotic therapy.
Case presentation
A 66-year-old Japanese male patient had received regorafenib (160 mg/day) as an anticancer treatment for metastatic colorectal carcinoma. His medical history included hypertension, diabetes mellitus, dyslipidemia, chronic heart failure, deep vein thrombosis (DVT), and permanent pacemaker implantation due to complete atrioventricular block. His DVT had been managed with low-dose apixaban (5 mg/day; body weight: 75 kg, creatinine: 1.0 mg/dL) to avoid bleeding complications.
Two months ago, he had suffered from non-ST-elevation myocardial infarction with the high-lateral (HL) branch as the culprit lesion, accompanied by chest discomfort; the HL branch occlusion was treated with balloon dilation only to avoid the need of a long-term triple antithrombotic therapy. At the same time, coronary angiography (CAG) revealed severe stenosis in the proximal left anterior descending (LAD) artery. A fractional flow reserve value of 0.72 confirmed a physiologically significant lesion. After PCI for the HL branch, regorafenib was withdrawn temporarily, and a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day) was successfully continued for two months without bleeding complications. Subsequently, the patient underwent PCI for severe stenosis in the LAD lesion two months after PCI for HL, as he demonstrated good tolerance to the triple antithrombotic therapy. Other medications administered included bisoprolol (1.25 mg/day), enalapril (2.5 mg/day), furosemide (20 mg/day), esomeprazole (20 mg/day), amlodipine (5 mg/day), sitagliptin (50 mg/day), mitiglinide (30 mg/day), and insulin degludec (9 units). In addition, routine blood testing revealed an elevated level of B-type natriuretic peptide (BNP), normal kidney function, high value of HbA1c, and mild anemia (BNP: 191.6 pg/mL, creatinine: 0.68 mg/dL, estimated glomerular filtration rate: 89.3 mL/minute/1.73 m2, HbA1c: 8.4%, hemoglobin: 9.9 g/dL, and platelet count: 318 × 103/µL). He was classified as having a high thrombotic and bleeding risk at this time, according to the CREDO-Kyoto thrombotic and bleeding risk scores. A sirolimus-eluting stent, which is a drug-eluting stent (DES) (Ultimaster Tansei 3.5/38 mm; Terumo Corporation, Tokyo, Japan), was implanted in the LAD lesion without malapposition or significant under-expansion, as confirmed by intravascular ultrasound imaging (IVUS) analysis (Fig. 1). After PCI for the LAD, regorafenib was resumed because it exhibited a clinical effect on the patient's cancer. Nevertheless, the patient was admitted to our hospital for congestive heart failure with dyspnea one month later (BNP: 1,512.5 pg/mL). Echocardiography demonstrated new severe hypokinesis of the anteroseptal wall and apex. Despite continued triple antithrombotic therapy, CAG revealed focal and eccentric contrastive defects in the previous LAD stent, and OFDI confirmed ST (Fig. 2a–e). A 3.5/20 mm perfusion balloon (Ryusei, Kaneka Medical, Tokyo, Japan) was inflated for 3 min using an embolic protection device (Fig. 2f). CAG and OFDI confirmed optimal initial gain in the ST site and thrombolysis in myocardial infarction flow grade 3, with no complications including distal emboli (Fig. 2g–k). Antithrombotic therapy was further enhanced temporarily to prevent the recurrence of ST; it included aspirin (100 mg/day), ticagrelor (120 mg/day), and apixaban (10 mg/day). The administration of regorafenib was discontinued after PCI for ST in the LAD, and aspirin and ticagrelor were discontinued 1 and 2 months later, respectively. No further thromboembolic events (including definite/probable ST) were observed, and heart failure was managed well. However, he died due to the progression of metastatic colorectal carcinoma about 3 months after ST onset.Fig. 1 Percutaneous coronary intervention for left anterior descending artery under intravascular ultrasound guidance. a, b Severe stenosis in the left anterior descending (LAD) artery (arrowhead) on initial coronary angiography (CAG). c Stent implantation in the LAD. d–g Final CAG showing an optimal result, with longitudinal and cross-sectional views in intravascular ultrasound imaging; acceptable stent expansion is confirmed
Fig. 2 Early stent thrombosis and revascularization. a Focal and eccentric contrastive defect in the previous left anterior descending stent. b–e Cross-sectional and longitudinal views of the stent thrombosis in optical frequency domain imaging (OFDI). f 3.5-mm perfusion balloon is dilated for 3 min. g Final coronary angiography reveals reduction of the contrastive defect and thrombolysis in myocardial infarction flow grade 3 without distal emboli. h–k Cross-sectional and longitudinal views in OFDI showing an increase in the lumen area and a small amount of residual thrombus
Discussion and conclusions
In this modern stent-based PCI era, ST represents a fatal and life-threatening complication. According to previous reports, the risk of ST is strongly associated with both, the patient background and procedural aspects [1, 3]. Certain patient background factors are independent predictors of a bleeding risk; malignant disease is a strong risk factor for major bleeding after PCI, as well as ST [1]. Our patient was classified as having a high thrombotic (4 points: anemia, heart failure, diabetes mellitus) and bleeding (4 points: heart failure, prior myocardial infarction, malignancy) risk, according to the CREDO-Kyoto thrombotic and bleeding risk scores [3]. Thus, we always had to consider the tradeoffs between the thrombotic and bleeding risks and PCI while caring for him.
The most frequent optical coherence tomography findings in early ST (within 30 days after index PCI) are uncovered struts and under-expansion [4]. Incomplete neointimal coverage of the struts in the early phase is normal, but the risk of ST associated with this procedure needs to be minimized. This risk could be reduced by optimizing stent placement with intracoronary imaging techniques and developing newer DES technology [1]. Moreover, dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor blocker after coronary stent implantation has been effective in preventing ST, and has been the standard treatment. Regarding P2Y12 receptor blockers, prasugrel or ticagrelor, in combination with aspirin, has been associated with a greater reduction in ST as compared to a combination of clopidogrel and aspirin [5, 6]. Furthermore, among stented patients with acute coronary syndrome treated by DAPT, low-dose rivaroxaban administration has been associated with a reduction in ST [7]. Thus, antithrombotic therapy after PCI has been established worldwide, but the optimal duration of DAPT remains controversial. Recent global guidelines recommend a shorter duration of DAPT for clinical efficacy. Additionally, it is recommended that the duration of the combination of triple antithrombotic therapy with DAPT and oral anticoagulants be as brief as possible [8]. However, there remains a lack of discussion regarding an appropriate antiplatelet therapy after PCI for cancer patients who are or are not undergoing chemotherapy. In our patient, although new-generation DES implantation was optimized by IVUS and a more potent antithrombotic therapy (DAPT and direct oral anticoagulant [DOAC]) was continued, early ST still occurred. This suggests that a standardized antithrombotic drug reduction may cause life-threatening ST in cancer patients receiving chemotherapy. The patient in our case was managed by changing the P2Y12 receptor blocker, increasing the DOAC dose, and withdrawing regorafenib until an adequate neointimal coverage of the struts was achieved. Thus, the risk of ST and the optimal duration of DAPT in cancer patients undergoing chemotherapy should be explored further.
While the association between venous thromboembolism (VTE) and malignancy is well-discussed, arterial thrombosis has more recently been recognized as a serious complication of cancer and chemotherapy. One study, based on a large database in the USA, reported that the incidence of arterial thromboembolic events (ATEs) in patients with cancer at 6 months was 4.7% [9]; patients with lung, gastric, or pancreatic cancers had the highest rates of ATEs (8.3, 6.5, and 5.9%, respectively). Moreover, an advanced stage of cancer was associated with a significant increase in the incidence of ATEs (stage 0 vs. stage 4: 2.3% vs. 7.7% at 6 months). Furthermore, certain chemotherapeutic agents, including VEGF inhibitors, have been reported to be associated with ATEs [10]; cisplatin, nilotinib, ponatinib, 5-FU, and capecitabine are particularly associated with a high incidence of coronary artery thrombotic events. Thus, while determining the risk of ischemic events after PCI, physicians should take into account the type of cancer, progression, and chemotherapeutic regimen. Similarly, the risks of occurrence and recurrence of cancer-associated VTE were found to vary according to the type and spread of the malignant disease [11]. Recent clinical trials assessing DOACs for cancer-associated VTE reported that DOACs seemed to be a reasonable treatment for VTE in such patients [12]. However, it should be noted that in these trials, bleeding events occurred in cases with gastrointestinal and urological tumors; such an occurrence of bleeding events in different types of cancers may also apply to DAPT after PCI in cancer patients. The traditional stratification of risks for bleeding and ischemic events after coronary stent implantation may need to be supplemented with information on the cancer type, progression, and chemotherapeutic regimen.
Regorafenib, an oral multi-targeted receptor tyrosine kinase inhibitor that targets VEGF (thereby affecting cell proliferation and angiogenesis), has been indicated for metastatic colorectal carcinoma. However, it is associated with cardiovascular complications such as hypertension, hemorrhage, thrombosis, and heart failure [2, 10, 13]. Regorafenib was previously reported to be less involved in thrombosis as compared to similar drugs, and has been relatively well-tolerated by patients [13]. However, increased platelet activation, endothelial dysfunction, and dysfunctional nitric oxide metabolism due to VEGF inhibitors result in thrombosis, because VEGF is an important signaling factor for endothelial cell health, which is essential for blood vessel formation and maintenance [10]. Thus, VEGF is important for endothelial cell health and vascular repair in patients undergoing PCI. As a result, VEGF inhibitors, such as regorafenib, might be associated with ST. In our case, it was important to consider a change in the chemotherapeutic regimen before PCI. However, the patient wished to continue regorafenib, because it was an almost final-line treatment for his cancer. Oncology and cardiovascular experts should make every effort to provide optimal medical care while respecting the patients' wishes.
The management of hemodynamically significant CAD in cancer patients, especially those undergoing chemotherapy, has not been fully established. Optimal stent replacement during PCI under intracoronary imaging could reduce the risk of ST, but this may be insufficient. The optimal treatment strategy for cancer patients with CAD, including invasive revascularization, antithrombotic therapy, and chemotherapy, needs to be verified. Future developments in the field of cardio-oncology will need to adapt to changes in the patient population and focus on optimal prevention and surveillance strategies accordingly.
Abbreviations
ATEsarterial thromboembolic events
BNPB-type natriuretic peptide
CADcoronary artery disease
CAGcoronary angiography
DAPTdual-antiplatelet therapy
DESdrug-eluting stent
DOACdirect oral anticoagulant
DVTdeep venous thrombosis
HLhigh-lateral
OFDIoptical frequency domain imaging
IVUSintravascular ultrasound imaging
LADleft anterior descending
PCIpercutaneous coronary intervention
STstent thrombosis
VEGFvascular endothelial growth factor
VTEvenous thromboembolism
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KS and TO managed the patient and wrote and revised the manuscript. KY, KZ and SM revised the manuscript and figures. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and in its additional files.
Ethics approval and consent to participate
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or with comparable ethical standards.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images and videos. A copy of the written consent is available for review by the editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Fatal | ReactionOutcome | CC BY | 33516171 | 18,873,767 | 2021-01-30 |
What was the outcome of reaction 'Vascular stent thrombosis'? | Early stent thrombosis confirmed in a cancer patient receiving regorafenib, despite triple antithrombotic therapy: a case report.
While developments in oncology have lengthened survival in patients with cancer, such patients often develop cardiovascular diseases. Thus, percutaneous coronary intervention (PCI) is frequently undertaken in them. Although stent thrombosis remains a fatal complication in stent-based PCI, worldwide consensus panels tend to recommend shorter duration of dual-antiplatelet therapy. This is based on its clinical efficacy that has resulted from technological innovation. However, there is insufficient discussion on the risk of stent thrombosis in cancer patients with coronary artery disease, especially in those undergoing chemotherapeutic regimens that have a risk for thrombosis, such as regimens with the anti-vascular endothelial growth factor. Presented here is a case of early stent thrombosis that occurred in a cancer patient on regorafenib, despite the administration of triple antithrombotic therapy. Case presentation A 66-year-old Japanese male patient received regorafenib for metastatic colorectal carcinoma and apixaban for deep vein thrombosis. Coronary angiography revealed severe stenosis in the proximal left anterior descending artery. A sirolimus-eluting stent was implanted, without malapposition and under-expansion, under intravascular ultrasound guidance while administering a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day). However, he was admitted to the hospital for exacerbation of heart failure 1 month after PCI. Coronary angiography revealed contrastive defects in the previous stent. Optical frequency domain imaging confirmed stent thrombosis. PCI was successfully performed with perfusion balloon long-inflation. Antithrombotic therapy was enhanced (aspirin: 100 mg/day, ticagrelor: 120 mg/day, and apixaban: 10 mg/day) and regorafenib was discontinued permanently. While ischemic events did not occur thereafter, the patient died due to metastatic carcinoma progression.
This case suggests that anti-vascular endothelial growth factor might contribute to early stent thrombosis, despite triple antithrombotic therapy. Further discussion is needed on the surveillance and management of cancer patients with coronary artery disease receiving chemotherapy, which carries a risk of thrombosis.
Background
Cardio-oncology is a rapidly growing subspeciality worldwide. Recent oncological developments have led to favorable clinical outcomes in cancer patients; however, many cancer survivors develop cardiovascular diseases. As a result, percutaneous coronary intervention (PCI) is frequently performed in cancer patients, who also develop coronary artery disease (CAD) while receiving chemotherapy.
Stent thrombosis (ST) is a rare but serious complication of PCI. Malignant disease is known as a strong risk factor for the development of ST and hemorrhage after stent implantation [1]. In addition, many modern chemotherapies are associated with vascular complications such as thrombosis and major bleeding [2]. Cancer and its treatment with chemotherapy are associated with a potential risk of thrombotic and bleeding complications in patients undergoing PCI. However, currently, there is insufficient evidence for optimal prevention and risk stratification of ST in these patients.
Described below is a case of early ST that was confirmed by optical frequency domain imaging (OFDI). In this case, ST occurred in a cancer patient receiving anti-vascular endothelial growth factor (VEGF) therapy in our hospital despite the administration of a triple antithrombotic therapy.
Case presentation
A 66-year-old Japanese male patient had received regorafenib (160 mg/day) as an anticancer treatment for metastatic colorectal carcinoma. His medical history included hypertension, diabetes mellitus, dyslipidemia, chronic heart failure, deep vein thrombosis (DVT), and permanent pacemaker implantation due to complete atrioventricular block. His DVT had been managed with low-dose apixaban (5 mg/day; body weight: 75 kg, creatinine: 1.0 mg/dL) to avoid bleeding complications.
Two months ago, he had suffered from non-ST-elevation myocardial infarction with the high-lateral (HL) branch as the culprit lesion, accompanied by chest discomfort; the HL branch occlusion was treated with balloon dilation only to avoid the need of a long-term triple antithrombotic therapy. At the same time, coronary angiography (CAG) revealed severe stenosis in the proximal left anterior descending (LAD) artery. A fractional flow reserve value of 0.72 confirmed a physiologically significant lesion. After PCI for the HL branch, regorafenib was withdrawn temporarily, and a triple antithrombotic therapy (aspirin: 100 mg/day, prasugrel: 3.75 mg/day, and apixaban: 5 mg/day) was successfully continued for two months without bleeding complications. Subsequently, the patient underwent PCI for severe stenosis in the LAD lesion two months after PCI for HL, as he demonstrated good tolerance to the triple antithrombotic therapy. Other medications administered included bisoprolol (1.25 mg/day), enalapril (2.5 mg/day), furosemide (20 mg/day), esomeprazole (20 mg/day), amlodipine (5 mg/day), sitagliptin (50 mg/day), mitiglinide (30 mg/day), and insulin degludec (9 units). In addition, routine blood testing revealed an elevated level of B-type natriuretic peptide (BNP), normal kidney function, high value of HbA1c, and mild anemia (BNP: 191.6 pg/mL, creatinine: 0.68 mg/dL, estimated glomerular filtration rate: 89.3 mL/minute/1.73 m2, HbA1c: 8.4%, hemoglobin: 9.9 g/dL, and platelet count: 318 × 103/µL). He was classified as having a high thrombotic and bleeding risk at this time, according to the CREDO-Kyoto thrombotic and bleeding risk scores. A sirolimus-eluting stent, which is a drug-eluting stent (DES) (Ultimaster Tansei 3.5/38 mm; Terumo Corporation, Tokyo, Japan), was implanted in the LAD lesion without malapposition or significant under-expansion, as confirmed by intravascular ultrasound imaging (IVUS) analysis (Fig. 1). After PCI for the LAD, regorafenib was resumed because it exhibited a clinical effect on the patient's cancer. Nevertheless, the patient was admitted to our hospital for congestive heart failure with dyspnea one month later (BNP: 1,512.5 pg/mL). Echocardiography demonstrated new severe hypokinesis of the anteroseptal wall and apex. Despite continued triple antithrombotic therapy, CAG revealed focal and eccentric contrastive defects in the previous LAD stent, and OFDI confirmed ST (Fig. 2a–e). A 3.5/20 mm perfusion balloon (Ryusei, Kaneka Medical, Tokyo, Japan) was inflated for 3 min using an embolic protection device (Fig. 2f). CAG and OFDI confirmed optimal initial gain in the ST site and thrombolysis in myocardial infarction flow grade 3, with no complications including distal emboli (Fig. 2g–k). Antithrombotic therapy was further enhanced temporarily to prevent the recurrence of ST; it included aspirin (100 mg/day), ticagrelor (120 mg/day), and apixaban (10 mg/day). The administration of regorafenib was discontinued after PCI for ST in the LAD, and aspirin and ticagrelor were discontinued 1 and 2 months later, respectively. No further thromboembolic events (including definite/probable ST) were observed, and heart failure was managed well. However, he died due to the progression of metastatic colorectal carcinoma about 3 months after ST onset.Fig. 1 Percutaneous coronary intervention for left anterior descending artery under intravascular ultrasound guidance. a, b Severe stenosis in the left anterior descending (LAD) artery (arrowhead) on initial coronary angiography (CAG). c Stent implantation in the LAD. d–g Final CAG showing an optimal result, with longitudinal and cross-sectional views in intravascular ultrasound imaging; acceptable stent expansion is confirmed
Fig. 2 Early stent thrombosis and revascularization. a Focal and eccentric contrastive defect in the previous left anterior descending stent. b–e Cross-sectional and longitudinal views of the stent thrombosis in optical frequency domain imaging (OFDI). f 3.5-mm perfusion balloon is dilated for 3 min. g Final coronary angiography reveals reduction of the contrastive defect and thrombolysis in myocardial infarction flow grade 3 without distal emboli. h–k Cross-sectional and longitudinal views in OFDI showing an increase in the lumen area and a small amount of residual thrombus
Discussion and conclusions
In this modern stent-based PCI era, ST represents a fatal and life-threatening complication. According to previous reports, the risk of ST is strongly associated with both, the patient background and procedural aspects [1, 3]. Certain patient background factors are independent predictors of a bleeding risk; malignant disease is a strong risk factor for major bleeding after PCI, as well as ST [1]. Our patient was classified as having a high thrombotic (4 points: anemia, heart failure, diabetes mellitus) and bleeding (4 points: heart failure, prior myocardial infarction, malignancy) risk, according to the CREDO-Kyoto thrombotic and bleeding risk scores [3]. Thus, we always had to consider the tradeoffs between the thrombotic and bleeding risks and PCI while caring for him.
The most frequent optical coherence tomography findings in early ST (within 30 days after index PCI) are uncovered struts and under-expansion [4]. Incomplete neointimal coverage of the struts in the early phase is normal, but the risk of ST associated with this procedure needs to be minimized. This risk could be reduced by optimizing stent placement with intracoronary imaging techniques and developing newer DES technology [1]. Moreover, dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor blocker after coronary stent implantation has been effective in preventing ST, and has been the standard treatment. Regarding P2Y12 receptor blockers, prasugrel or ticagrelor, in combination with aspirin, has been associated with a greater reduction in ST as compared to a combination of clopidogrel and aspirin [5, 6]. Furthermore, among stented patients with acute coronary syndrome treated by DAPT, low-dose rivaroxaban administration has been associated with a reduction in ST [7]. Thus, antithrombotic therapy after PCI has been established worldwide, but the optimal duration of DAPT remains controversial. Recent global guidelines recommend a shorter duration of DAPT for clinical efficacy. Additionally, it is recommended that the duration of the combination of triple antithrombotic therapy with DAPT and oral anticoagulants be as brief as possible [8]. However, there remains a lack of discussion regarding an appropriate antiplatelet therapy after PCI for cancer patients who are or are not undergoing chemotherapy. In our patient, although new-generation DES implantation was optimized by IVUS and a more potent antithrombotic therapy (DAPT and direct oral anticoagulant [DOAC]) was continued, early ST still occurred. This suggests that a standardized antithrombotic drug reduction may cause life-threatening ST in cancer patients receiving chemotherapy. The patient in our case was managed by changing the P2Y12 receptor blocker, increasing the DOAC dose, and withdrawing regorafenib until an adequate neointimal coverage of the struts was achieved. Thus, the risk of ST and the optimal duration of DAPT in cancer patients undergoing chemotherapy should be explored further.
While the association between venous thromboembolism (VTE) and malignancy is well-discussed, arterial thrombosis has more recently been recognized as a serious complication of cancer and chemotherapy. One study, based on a large database in the USA, reported that the incidence of arterial thromboembolic events (ATEs) in patients with cancer at 6 months was 4.7% [9]; patients with lung, gastric, or pancreatic cancers had the highest rates of ATEs (8.3, 6.5, and 5.9%, respectively). Moreover, an advanced stage of cancer was associated with a significant increase in the incidence of ATEs (stage 0 vs. stage 4: 2.3% vs. 7.7% at 6 months). Furthermore, certain chemotherapeutic agents, including VEGF inhibitors, have been reported to be associated with ATEs [10]; cisplatin, nilotinib, ponatinib, 5-FU, and capecitabine are particularly associated with a high incidence of coronary artery thrombotic events. Thus, while determining the risk of ischemic events after PCI, physicians should take into account the type of cancer, progression, and chemotherapeutic regimen. Similarly, the risks of occurrence and recurrence of cancer-associated VTE were found to vary according to the type and spread of the malignant disease [11]. Recent clinical trials assessing DOACs for cancer-associated VTE reported that DOACs seemed to be a reasonable treatment for VTE in such patients [12]. However, it should be noted that in these trials, bleeding events occurred in cases with gastrointestinal and urological tumors; such an occurrence of bleeding events in different types of cancers may also apply to DAPT after PCI in cancer patients. The traditional stratification of risks for bleeding and ischemic events after coronary stent implantation may need to be supplemented with information on the cancer type, progression, and chemotherapeutic regimen.
Regorafenib, an oral multi-targeted receptor tyrosine kinase inhibitor that targets VEGF (thereby affecting cell proliferation and angiogenesis), has been indicated for metastatic colorectal carcinoma. However, it is associated with cardiovascular complications such as hypertension, hemorrhage, thrombosis, and heart failure [2, 10, 13]. Regorafenib was previously reported to be less involved in thrombosis as compared to similar drugs, and has been relatively well-tolerated by patients [13]. However, increased platelet activation, endothelial dysfunction, and dysfunctional nitric oxide metabolism due to VEGF inhibitors result in thrombosis, because VEGF is an important signaling factor for endothelial cell health, which is essential for blood vessel formation and maintenance [10]. Thus, VEGF is important for endothelial cell health and vascular repair in patients undergoing PCI. As a result, VEGF inhibitors, such as regorafenib, might be associated with ST. In our case, it was important to consider a change in the chemotherapeutic regimen before PCI. However, the patient wished to continue regorafenib, because it was an almost final-line treatment for his cancer. Oncology and cardiovascular experts should make every effort to provide optimal medical care while respecting the patients' wishes.
The management of hemodynamically significant CAD in cancer patients, especially those undergoing chemotherapy, has not been fully established. Optimal stent replacement during PCI under intracoronary imaging could reduce the risk of ST, but this may be insufficient. The optimal treatment strategy for cancer patients with CAD, including invasive revascularization, antithrombotic therapy, and chemotherapy, needs to be verified. Future developments in the field of cardio-oncology will need to adapt to changes in the patient population and focus on optimal prevention and surveillance strategies accordingly.
Abbreviations
ATEsarterial thromboembolic events
BNPB-type natriuretic peptide
CADcoronary artery disease
CAGcoronary angiography
DAPTdual-antiplatelet therapy
DESdrug-eluting stent
DOACdirect oral anticoagulant
DVTdeep venous thrombosis
HLhigh-lateral
OFDIoptical frequency domain imaging
IVUSintravascular ultrasound imaging
LADleft anterior descending
PCIpercutaneous coronary intervention
STstent thrombosis
VEGFvascular endothelial growth factor
VTEvenous thromboembolism
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
KS and TO managed the patient and wrote and revised the manuscript. KY, KZ and SM revised the manuscript and figures. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and in its additional files.
Ethics approval and consent to participate
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or with comparable ethical standards.
Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images and videos. A copy of the written consent is available for review by the editor of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33516171 | 18,873,767 | 2021-01-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Clonal evolution'. | Outgrowth of a CSF3R-mutant clone drives a second myeloproliferative neoplasm in a chronic myeloid leukemia patient: a case report.
BACKGROUND
Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two myeloproliferative neoplasms with mutually exclusive diagnostic criteria. A hallmark of CML is the Philadelphia chromosome (Ph), which results in a BCR-ABL1 fusion gene and constitutive tyrosine kinase activity. CNL is a Ph-negative neoplasm and is defined in part by the presence of CSF3R mutations, which drive constative JAK/STAT signaling.
METHODS
Here, we report the exceedingly rare co-occurrence of two granulocytic myeloproliferative neoplasms in a 69-year old male patient. After an initial diagnosis of chronic myeloid leukemia, the patient's clinical course was shaped by hematologic toxicity, the emergence of treatment-resistant BCR-ABL1 clones, and the expansion of a CSF3R-mutant clone without ABL1 mutations under selective pressure from tyrosine kinase inhibitors. The emergence of the CSF3R-mutant, neutrophilic clone led to the diagnosis of CNL as a second myeloproliferative neoplasm in the same patient.
CONCLUSIONS
This is the first reported case of CNL arising subsequent to CML, which occurred under selective pressure from targeted therapy in a patient with complex clonal architecture. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Background
Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies in which a hematopoietic stem cell defect drives proliferation of mature myeloid cell lineages. Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two MPNs with mutually exclusive diagnostic criteria. A hallmark of CML is the presence of the Philadelphia (Ph) chromosome, which results from t (9;22) and separates CML from Ph-negative MPNs: essential thrombocythemia, primary myelofibrosis, polycythemia vera, chronic neutrophilic leukemia [1]. The BCR-ABL1 fusion gene results from t (9;22) and drives the proliferation of mature myeloid cells through constitutive tyrosine kinase activity [2, 3]. In this report, we describe a second rare MPN, chronic neutrophilic leukemia (CNL), arising after a CML patient achieved a complete molecular remission. This is the first reported case of CNL arising subsequent to CML.
Case presentation
A 69-year-old presented initially to his primary care provider with a progressive cough accompanied by weakness, fatigue, and abdominal distension. His white cell count was 113,900/mm3, hemoglobin was 11.8 g/dL, and platelet count was 325,000/mm3. A bone marrow biopsy showed a markedly hypercellular marrow (100%) with ~ 4% blasts, consistent with chronic phase CML. A 300 cell differential showed left-shifted myelopoiesis in which mid-range differentiated granulocytes—myelocytes, metamyelocytes with lesser amounts of promyelocytes—predominated over more differentiated forms. Myeloid and erythroid precursors were present in a 20:1 ratio. Auer rods were not observed. A Fluorescent In Situ Hybridization (FISH) assay confirmed a BCR-ABL1 translocation and cytogenetics revealed the Ph chromosome resulting from a (9;22) translocation. The major BCR-ABL1 transcript (p210) was 66.45% on the international scale (IS). The patient was started on 300 mg of nilotinib twice daily, which reduced his BCR-ABL1 to 0.403% (IS) in 18 weeks. However, the emergence of six new pathogenic mutations as well as hematologic toxicity of ABL1 inhibitors in this case made the treatment course complex (Tables 1, 2).
Table 1 Treatment strategy. The patient had difficulty tolerating TKIs due to hematologic toxicity (thrombocytopenia). Additionally, identification of three genetic variants triggered three treatment changes: imatinib and nilotinib-resistant BCR-ABL1 E255V, ponatinib-sensitive BCR-ABL1 T315I, ruxolitinib-sensitive CSF3R mutations. Dates initiated and discontinued are the number of weeks post-diagnosis of CML
Inhibitor Molecular Target Initiated Discontinued Reason Discontinued
Nilotinib BCR-ABL1 0w 28w Thrombocytopenia
Imatinib BCR-ABL1 33w 78w BCR-ABL1 p.E255V
Dasatinib BCR-ABL1 79w 118w BCR-ABL1 p.T315I
Ponatinib BCR-ABL1 128w
Ruxolitinib CSF3R 252w
Table 2 Variant allele frequencies and BCR-ABL transcript levels 3 years apart for predicted pathogenic mutations. Outgrowth of a CSF3R-mutant clone during treatment with BCR-ABL1 tyrosine kinase inhibitors drives disease evolution from CML to CNL
Gene Variant COSMIC v92
FATHMM prediction Variant Allele Frequency
69 weeks 116 weeks 225 weeks
KMT2C/MLL3 S1860C Pathogenic (score 0.90) 50.62 48.92
CSF3R T618I Pathogenic (score 0.96) 11.58 41.09
CSF3R W818* Pathogenic (score 0.83) 10.22 40.26
TET2 R1167K Pathogenic (score 0.99) 2.86
ABL1 E255V (not annotated) 2.01 Not detected (targeted PCR)
ABL1 T3151 (not annotated) Detected (targeted PCR)
BCR-ABL1 2.50% (IS) 0.508% (IS) 0.000% (IS)
After 18 weeks on nilotinib, the patient presented with chest pain and was found to have pericarditis, atrial fibrillation, and severe thrombocytopenia (platelets at 11,000). The patient was ultimately started on imatinib at 400 mg/day but thrombocytopenia remained problematic. After 2 months, imatinib was reduced to 300 mg/day in an attempt to stabilize the patient’s ongoing thrombocytopenia. His platelets only slightly improved, however BCR-ABL1 transcripts decreased. The 400 mg/day dose was resumed when BCR-ABL1 rose from 0.68 to 2.74% (IS); however, subsequent ABL sequencing detected an imatinib and nilotinib-resistant E255V mutation [4], and the patient switched to dasatinib at 100 mg/day.
The leukemia responded well to dasatinib, though BCR-ABL1 transcript level plateaued above 0.1% (IS), the threshold for a major molecular response. ABL sequencing after 9 months of treatment detected a T315I mutation, which confers resistance to dasatinib, nilotinib, imatinib and bosutinib [5–11]. The patient was switched to ponatinib (30 mg/day) and his BCR-ABL1 transcript levels decreased steadily, falling below 0.1% (IS) after 3 months. The patient tolerated ponatinib well, with no thrombocytopenia. After 2 years on ponatinib, the (9;22) translocation was not detected by FISH in 200 cells scored for BCR (22Q11.2)/ABL (9Q34). Additionally, the BCR-ABL1 fusion gene was no longer detectable by PCR, 0.000% (IS). After 2.5 years, the dose of ponatinib was reduced to 15 mg/day.
Despite the disappearance of the Ph chromosome, the patient’s white blood cell and absolute neutrophil counts rose while on ponatinib, raising concerns about whether a second Ph-negative MPN could be emerging (Fig. 1). A 220 gene next generation sequencing panel was ordered and two CSF3R mutations, T618I and W818*, were identified at a variant allele frequency (VAF) of 41.1 and 40.3%, respectively. Predicted pathogenic variants were identified based on the COSMIC v92 (Catalogue of Somatic Mutations in Cancer) database. Retrospective analysis of an archived marrow sample revealed that the CSF3R mutations had been present for at least the past 3 years. Bone marrow from diagnosis was not available for retrospective next generation sequencing analyses. In total, six predicted-pathogenic variants were detected in the patient over the course of his treatment, including two CSF3R mutations (T618I and W818*), two ABL1 mutations (E255V and T315I), KMT2C/MLL3 (S1860C), and TET2 (R1167K) (Table 2).
Fig. 1 Emergence of a CSF3R-mutant, neutrophilic leukemia during targeted therapy for BCR-ABL1. Hematologic toxicity and the emergence of treatment-resistant clones shaped this CML patient’s clinical course. Ultimately, treatment with ponatinib successfully controlled the BCR-ABL1 clone, while another neutrophilic clone containing CSF3R mutations, but not BCR-ABL1, expanded
CSF3R mutations are a hallmark of chronic neutrophilic leukemia (CNL), a rare MPN defined by persistent mature neutrophilic leukocytosis. When the CSF3R variants were detected, the patient’s WBC was 22,800/mm3 with 83% neutrophils, within the range of WHO-defined CNL (11,000–126,000/mm3, median 39,000/mm3). The patient was started on ruxolitinib (5 mg twice daily), which demonstrated efficacy against CNL and CSF3R-mutant atypical CML in a recent clinical trial [12, 13]. With ruxolitinib, the patient’s WBC count decreased slightly and stabilized between 12,800-17,400/mm3, absolute neutrophils between 9700 and 14,300/mm3, platelets were stable at 124,000-155,000/mm3, hemoglobin at 15.3–16.6 g/dL, hematocrit at 46.6–51%. Ruxolitinib was increased to 7.5 mg twice daily after 7 months, which lowered his WBC (8900-13,000/mm3) and absolute neutrophil (6300-10,000/mm3) counts further. At 5.8 years post CML diagnosis and 3.5 years on ponatinib, a third FISH analysis was performed and the (9;22) translocation was still not detectable (200 nuclei).
Discussion and conclusions
This patient had difficulty tolerating tyrosine kinase inhibitors (TKIs), primarily due to hematologic toxicity. While thrombocytopenia is a known side effect of TKIs, the severity and protracted nature of the side effect in this instance suggests dysfunction in the residual BCR-ABL1 negative stem cells. In this case, the emergence of six predicted-pathogenetic variants over the five-year course of treatment suggests that the patient either had a markedly elevated mutational load prior to diagnosis—with different clones emerging in response to TKI selection—or a propensity to develop mutations beyond what is normally associated with aging.
The mutations in BCR-ABL1 and TET2 were present at similar variant allele frequencies at 69 weeks and lost during treatment with dasatinib and ponatinib, suggesting they were present in the same clone. Meanwhile, the CSF3R-mutant clone expanded during BCR-ABL1-directed therapy and is likely independent. Given that the increase in neutrophils began when the patient was switched from dasatinib to ponatinib, it is plausible that the expansion of this clone occurred during treatment with ponatinib specifically. It is known that CSF3R truncating mutations are sensitive to dasatinib [14], and that may have contributed to a delayed onset of this second MPN.
It is well established that selective pressure from TKIs allows for the outgrowth of BCR-ABL1 clones harboring point mutations in ABL1. However, this study suggests that the clearance of a BCR-ABL1 positive clone allowed for the outgrowth of a second, genetically distinct leukemia. It is interesting to note that two granulocytic leukemias arose in this patient, suggesting that either cell intrinsic or microenvironmental factors caused a specific predilection for malignancies of the granulocytic lineage. Germline mutations have not been accessed for this patient. This case describes the exceedingly rare co-occurrence of CML and CNL in the same individual and is an unusual example of clonal evolution under selective pressure from targeted therapy. These findings highlight that myeloid disease with complex clonal architecture is prone to molecular evolution. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Abbreviations
MPNsMyeloproliferative neoplasms
CMLChronic myeloid leukemia
CNLChronic neutrophilic leukemia
PhPhiladelphia
FISHChromosome, Fluorescent In Situ Hybridization
ISInternational scale
TKIsTyrosine kinase inhibitors
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Authors thank colleagues at Arizona Center for Cancer Care and Grande Ronde Hospital for collaboration on the care of the patient.
Authors’ contributions
DB and BJD treated the patient; SAC, TPB and JEM analyzed and/or interpreted the data; SAC and TPB wrote the paper. All authors reviewed and approved the manuscript.
Funding
SAC is supported by a fellowship from the National Cancer Institute, F32CA239422. JEM is supported by an American Society of Hematology Scholar Award, a Gilead Research Scholars Award, and American Cancer Society RSG-19-184-01-LIB. TPB is supported by KL2 TR002370–03 and K08 CA245224–01. BJD is supported by Howard Hughes Medical Institute and R01 CA065823–24.
Availability of data and materials
Data sharing requests should be sent to the corresponding author.
Ethics approval and consent to participate
The OHSU IRB determined that the proposed activity is not research involving human subjects. Access and use of protected health information complies with OHSU HIPAA policies for non-research activities.
Consent for publication
Not applicable. Data presented in this study has been de-identified and contains none of the 18 HIPPA individual identifiers.
Competing interests
B.J.D. potential competing interests–SAB: Aileron Therapeutics, ALLCRON, Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Baxalta (inactive), Monojul (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, Third Coast Therapeutics, GRAIL (inactive), CTI BioPharma (inactive); scientific founder: MolecularMD (inactive, acquired by ICON); board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; founder: VP Therapeutics; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana- Farber Cancer Institute (one Merck exclusive license). B.J.D. potential competing interests– consultant: Monojul, Patient True Talk; SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI Bio-Pharma (inactive); scientific founder and stock: MolecularMD; board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties: OHSU #606-Novartis exclusive license, OHSU #2573; Dana-Farber Cancer Institute #2063- Merck exclusive license. J.E.M. receives grant funding from the Gilead Research Scholars Program. The remaining authors declare no competing interests. | PONATINIB | DrugsGivenReaction | CC BY | 33516272 | 19,168,698 | 2021-01-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gene mutation'. | Outgrowth of a CSF3R-mutant clone drives a second myeloproliferative neoplasm in a chronic myeloid leukemia patient: a case report.
BACKGROUND
Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two myeloproliferative neoplasms with mutually exclusive diagnostic criteria. A hallmark of CML is the Philadelphia chromosome (Ph), which results in a BCR-ABL1 fusion gene and constitutive tyrosine kinase activity. CNL is a Ph-negative neoplasm and is defined in part by the presence of CSF3R mutations, which drive constative JAK/STAT signaling.
METHODS
Here, we report the exceedingly rare co-occurrence of two granulocytic myeloproliferative neoplasms in a 69-year old male patient. After an initial diagnosis of chronic myeloid leukemia, the patient's clinical course was shaped by hematologic toxicity, the emergence of treatment-resistant BCR-ABL1 clones, and the expansion of a CSF3R-mutant clone without ABL1 mutations under selective pressure from tyrosine kinase inhibitors. The emergence of the CSF3R-mutant, neutrophilic clone led to the diagnosis of CNL as a second myeloproliferative neoplasm in the same patient.
CONCLUSIONS
This is the first reported case of CNL arising subsequent to CML, which occurred under selective pressure from targeted therapy in a patient with complex clonal architecture. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Background
Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies in which a hematopoietic stem cell defect drives proliferation of mature myeloid cell lineages. Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two MPNs with mutually exclusive diagnostic criteria. A hallmark of CML is the presence of the Philadelphia (Ph) chromosome, which results from t (9;22) and separates CML from Ph-negative MPNs: essential thrombocythemia, primary myelofibrosis, polycythemia vera, chronic neutrophilic leukemia [1]. The BCR-ABL1 fusion gene results from t (9;22) and drives the proliferation of mature myeloid cells through constitutive tyrosine kinase activity [2, 3]. In this report, we describe a second rare MPN, chronic neutrophilic leukemia (CNL), arising after a CML patient achieved a complete molecular remission. This is the first reported case of CNL arising subsequent to CML.
Case presentation
A 69-year-old presented initially to his primary care provider with a progressive cough accompanied by weakness, fatigue, and abdominal distension. His white cell count was 113,900/mm3, hemoglobin was 11.8 g/dL, and platelet count was 325,000/mm3. A bone marrow biopsy showed a markedly hypercellular marrow (100%) with ~ 4% blasts, consistent with chronic phase CML. A 300 cell differential showed left-shifted myelopoiesis in which mid-range differentiated granulocytes—myelocytes, metamyelocytes with lesser amounts of promyelocytes—predominated over more differentiated forms. Myeloid and erythroid precursors were present in a 20:1 ratio. Auer rods were not observed. A Fluorescent In Situ Hybridization (FISH) assay confirmed a BCR-ABL1 translocation and cytogenetics revealed the Ph chromosome resulting from a (9;22) translocation. The major BCR-ABL1 transcript (p210) was 66.45% on the international scale (IS). The patient was started on 300 mg of nilotinib twice daily, which reduced his BCR-ABL1 to 0.403% (IS) in 18 weeks. However, the emergence of six new pathogenic mutations as well as hematologic toxicity of ABL1 inhibitors in this case made the treatment course complex (Tables 1, 2).
Table 1 Treatment strategy. The patient had difficulty tolerating TKIs due to hematologic toxicity (thrombocytopenia). Additionally, identification of three genetic variants triggered three treatment changes: imatinib and nilotinib-resistant BCR-ABL1 E255V, ponatinib-sensitive BCR-ABL1 T315I, ruxolitinib-sensitive CSF3R mutations. Dates initiated and discontinued are the number of weeks post-diagnosis of CML
Inhibitor Molecular Target Initiated Discontinued Reason Discontinued
Nilotinib BCR-ABL1 0w 28w Thrombocytopenia
Imatinib BCR-ABL1 33w 78w BCR-ABL1 p.E255V
Dasatinib BCR-ABL1 79w 118w BCR-ABL1 p.T315I
Ponatinib BCR-ABL1 128w
Ruxolitinib CSF3R 252w
Table 2 Variant allele frequencies and BCR-ABL transcript levels 3 years apart for predicted pathogenic mutations. Outgrowth of a CSF3R-mutant clone during treatment with BCR-ABL1 tyrosine kinase inhibitors drives disease evolution from CML to CNL
Gene Variant COSMIC v92
FATHMM prediction Variant Allele Frequency
69 weeks 116 weeks 225 weeks
KMT2C/MLL3 S1860C Pathogenic (score 0.90) 50.62 48.92
CSF3R T618I Pathogenic (score 0.96) 11.58 41.09
CSF3R W818* Pathogenic (score 0.83) 10.22 40.26
TET2 R1167K Pathogenic (score 0.99) 2.86
ABL1 E255V (not annotated) 2.01 Not detected (targeted PCR)
ABL1 T3151 (not annotated) Detected (targeted PCR)
BCR-ABL1 2.50% (IS) 0.508% (IS) 0.000% (IS)
After 18 weeks on nilotinib, the patient presented with chest pain and was found to have pericarditis, atrial fibrillation, and severe thrombocytopenia (platelets at 11,000). The patient was ultimately started on imatinib at 400 mg/day but thrombocytopenia remained problematic. After 2 months, imatinib was reduced to 300 mg/day in an attempt to stabilize the patient’s ongoing thrombocytopenia. His platelets only slightly improved, however BCR-ABL1 transcripts decreased. The 400 mg/day dose was resumed when BCR-ABL1 rose from 0.68 to 2.74% (IS); however, subsequent ABL sequencing detected an imatinib and nilotinib-resistant E255V mutation [4], and the patient switched to dasatinib at 100 mg/day.
The leukemia responded well to dasatinib, though BCR-ABL1 transcript level plateaued above 0.1% (IS), the threshold for a major molecular response. ABL sequencing after 9 months of treatment detected a T315I mutation, which confers resistance to dasatinib, nilotinib, imatinib and bosutinib [5–11]. The patient was switched to ponatinib (30 mg/day) and his BCR-ABL1 transcript levels decreased steadily, falling below 0.1% (IS) after 3 months. The patient tolerated ponatinib well, with no thrombocytopenia. After 2 years on ponatinib, the (9;22) translocation was not detected by FISH in 200 cells scored for BCR (22Q11.2)/ABL (9Q34). Additionally, the BCR-ABL1 fusion gene was no longer detectable by PCR, 0.000% (IS). After 2.5 years, the dose of ponatinib was reduced to 15 mg/day.
Despite the disappearance of the Ph chromosome, the patient’s white blood cell and absolute neutrophil counts rose while on ponatinib, raising concerns about whether a second Ph-negative MPN could be emerging (Fig. 1). A 220 gene next generation sequencing panel was ordered and two CSF3R mutations, T618I and W818*, were identified at a variant allele frequency (VAF) of 41.1 and 40.3%, respectively. Predicted pathogenic variants were identified based on the COSMIC v92 (Catalogue of Somatic Mutations in Cancer) database. Retrospective analysis of an archived marrow sample revealed that the CSF3R mutations had been present for at least the past 3 years. Bone marrow from diagnosis was not available for retrospective next generation sequencing analyses. In total, six predicted-pathogenic variants were detected in the patient over the course of his treatment, including two CSF3R mutations (T618I and W818*), two ABL1 mutations (E255V and T315I), KMT2C/MLL3 (S1860C), and TET2 (R1167K) (Table 2).
Fig. 1 Emergence of a CSF3R-mutant, neutrophilic leukemia during targeted therapy for BCR-ABL1. Hematologic toxicity and the emergence of treatment-resistant clones shaped this CML patient’s clinical course. Ultimately, treatment with ponatinib successfully controlled the BCR-ABL1 clone, while another neutrophilic clone containing CSF3R mutations, but not BCR-ABL1, expanded
CSF3R mutations are a hallmark of chronic neutrophilic leukemia (CNL), a rare MPN defined by persistent mature neutrophilic leukocytosis. When the CSF3R variants were detected, the patient’s WBC was 22,800/mm3 with 83% neutrophils, within the range of WHO-defined CNL (11,000–126,000/mm3, median 39,000/mm3). The patient was started on ruxolitinib (5 mg twice daily), which demonstrated efficacy against CNL and CSF3R-mutant atypical CML in a recent clinical trial [12, 13]. With ruxolitinib, the patient’s WBC count decreased slightly and stabilized between 12,800-17,400/mm3, absolute neutrophils between 9700 and 14,300/mm3, platelets were stable at 124,000-155,000/mm3, hemoglobin at 15.3–16.6 g/dL, hematocrit at 46.6–51%. Ruxolitinib was increased to 7.5 mg twice daily after 7 months, which lowered his WBC (8900-13,000/mm3) and absolute neutrophil (6300-10,000/mm3) counts further. At 5.8 years post CML diagnosis and 3.5 years on ponatinib, a third FISH analysis was performed and the (9;22) translocation was still not detectable (200 nuclei).
Discussion and conclusions
This patient had difficulty tolerating tyrosine kinase inhibitors (TKIs), primarily due to hematologic toxicity. While thrombocytopenia is a known side effect of TKIs, the severity and protracted nature of the side effect in this instance suggests dysfunction in the residual BCR-ABL1 negative stem cells. In this case, the emergence of six predicted-pathogenetic variants over the five-year course of treatment suggests that the patient either had a markedly elevated mutational load prior to diagnosis—with different clones emerging in response to TKI selection—or a propensity to develop mutations beyond what is normally associated with aging.
The mutations in BCR-ABL1 and TET2 were present at similar variant allele frequencies at 69 weeks and lost during treatment with dasatinib and ponatinib, suggesting they were present in the same clone. Meanwhile, the CSF3R-mutant clone expanded during BCR-ABL1-directed therapy and is likely independent. Given that the increase in neutrophils began when the patient was switched from dasatinib to ponatinib, it is plausible that the expansion of this clone occurred during treatment with ponatinib specifically. It is known that CSF3R truncating mutations are sensitive to dasatinib [14], and that may have contributed to a delayed onset of this second MPN.
It is well established that selective pressure from TKIs allows for the outgrowth of BCR-ABL1 clones harboring point mutations in ABL1. However, this study suggests that the clearance of a BCR-ABL1 positive clone allowed for the outgrowth of a second, genetically distinct leukemia. It is interesting to note that two granulocytic leukemias arose in this patient, suggesting that either cell intrinsic or microenvironmental factors caused a specific predilection for malignancies of the granulocytic lineage. Germline mutations have not been accessed for this patient. This case describes the exceedingly rare co-occurrence of CML and CNL in the same individual and is an unusual example of clonal evolution under selective pressure from targeted therapy. These findings highlight that myeloid disease with complex clonal architecture is prone to molecular evolution. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Abbreviations
MPNsMyeloproliferative neoplasms
CMLChronic myeloid leukemia
CNLChronic neutrophilic leukemia
PhPhiladelphia
FISHChromosome, Fluorescent In Situ Hybridization
ISInternational scale
TKIsTyrosine kinase inhibitors
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Authors thank colleagues at Arizona Center for Cancer Care and Grande Ronde Hospital for collaboration on the care of the patient.
Authors’ contributions
DB and BJD treated the patient; SAC, TPB and JEM analyzed and/or interpreted the data; SAC and TPB wrote the paper. All authors reviewed and approved the manuscript.
Funding
SAC is supported by a fellowship from the National Cancer Institute, F32CA239422. JEM is supported by an American Society of Hematology Scholar Award, a Gilead Research Scholars Award, and American Cancer Society RSG-19-184-01-LIB. TPB is supported by KL2 TR002370–03 and K08 CA245224–01. BJD is supported by Howard Hughes Medical Institute and R01 CA065823–24.
Availability of data and materials
Data sharing requests should be sent to the corresponding author.
Ethics approval and consent to participate
The OHSU IRB determined that the proposed activity is not research involving human subjects. Access and use of protected health information complies with OHSU HIPAA policies for non-research activities.
Consent for publication
Not applicable. Data presented in this study has been de-identified and contains none of the 18 HIPPA individual identifiers.
Competing interests
B.J.D. potential competing interests–SAB: Aileron Therapeutics, ALLCRON, Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Baxalta (inactive), Monojul (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, Third Coast Therapeutics, GRAIL (inactive), CTI BioPharma (inactive); scientific founder: MolecularMD (inactive, acquired by ICON); board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; founder: VP Therapeutics; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana- Farber Cancer Institute (one Merck exclusive license). B.J.D. potential competing interests– consultant: Monojul, Patient True Talk; SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI Bio-Pharma (inactive); scientific founder and stock: MolecularMD; board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties: OHSU #606-Novartis exclusive license, OHSU #2573; Dana-Farber Cancer Institute #2063- Merck exclusive license. J.E.M. receives grant funding from the Gilead Research Scholars Program. The remaining authors declare no competing interests. | DASATINIB, IMATINIB MESYLATE, NILOTINIB | DrugsGivenReaction | CC BY | 33516272 | 19,082,195 | 2021-01-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myeloproliferative neoplasm'. | Outgrowth of a CSF3R-mutant clone drives a second myeloproliferative neoplasm in a chronic myeloid leukemia patient: a case report.
BACKGROUND
Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two myeloproliferative neoplasms with mutually exclusive diagnostic criteria. A hallmark of CML is the Philadelphia chromosome (Ph), which results in a BCR-ABL1 fusion gene and constitutive tyrosine kinase activity. CNL is a Ph-negative neoplasm and is defined in part by the presence of CSF3R mutations, which drive constative JAK/STAT signaling.
METHODS
Here, we report the exceedingly rare co-occurrence of two granulocytic myeloproliferative neoplasms in a 69-year old male patient. After an initial diagnosis of chronic myeloid leukemia, the patient's clinical course was shaped by hematologic toxicity, the emergence of treatment-resistant BCR-ABL1 clones, and the expansion of a CSF3R-mutant clone without ABL1 mutations under selective pressure from tyrosine kinase inhibitors. The emergence of the CSF3R-mutant, neutrophilic clone led to the diagnosis of CNL as a second myeloproliferative neoplasm in the same patient.
CONCLUSIONS
This is the first reported case of CNL arising subsequent to CML, which occurred under selective pressure from targeted therapy in a patient with complex clonal architecture. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Background
Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies in which a hematopoietic stem cell defect drives proliferation of mature myeloid cell lineages. Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two MPNs with mutually exclusive diagnostic criteria. A hallmark of CML is the presence of the Philadelphia (Ph) chromosome, which results from t (9;22) and separates CML from Ph-negative MPNs: essential thrombocythemia, primary myelofibrosis, polycythemia vera, chronic neutrophilic leukemia [1]. The BCR-ABL1 fusion gene results from t (9;22) and drives the proliferation of mature myeloid cells through constitutive tyrosine kinase activity [2, 3]. In this report, we describe a second rare MPN, chronic neutrophilic leukemia (CNL), arising after a CML patient achieved a complete molecular remission. This is the first reported case of CNL arising subsequent to CML.
Case presentation
A 69-year-old presented initially to his primary care provider with a progressive cough accompanied by weakness, fatigue, and abdominal distension. His white cell count was 113,900/mm3, hemoglobin was 11.8 g/dL, and platelet count was 325,000/mm3. A bone marrow biopsy showed a markedly hypercellular marrow (100%) with ~ 4% blasts, consistent with chronic phase CML. A 300 cell differential showed left-shifted myelopoiesis in which mid-range differentiated granulocytes—myelocytes, metamyelocytes with lesser amounts of promyelocytes—predominated over more differentiated forms. Myeloid and erythroid precursors were present in a 20:1 ratio. Auer rods were not observed. A Fluorescent In Situ Hybridization (FISH) assay confirmed a BCR-ABL1 translocation and cytogenetics revealed the Ph chromosome resulting from a (9;22) translocation. The major BCR-ABL1 transcript (p210) was 66.45% on the international scale (IS). The patient was started on 300 mg of nilotinib twice daily, which reduced his BCR-ABL1 to 0.403% (IS) in 18 weeks. However, the emergence of six new pathogenic mutations as well as hematologic toxicity of ABL1 inhibitors in this case made the treatment course complex (Tables 1, 2).
Table 1 Treatment strategy. The patient had difficulty tolerating TKIs due to hematologic toxicity (thrombocytopenia). Additionally, identification of three genetic variants triggered three treatment changes: imatinib and nilotinib-resistant BCR-ABL1 E255V, ponatinib-sensitive BCR-ABL1 T315I, ruxolitinib-sensitive CSF3R mutations. Dates initiated and discontinued are the number of weeks post-diagnosis of CML
Inhibitor Molecular Target Initiated Discontinued Reason Discontinued
Nilotinib BCR-ABL1 0w 28w Thrombocytopenia
Imatinib BCR-ABL1 33w 78w BCR-ABL1 p.E255V
Dasatinib BCR-ABL1 79w 118w BCR-ABL1 p.T315I
Ponatinib BCR-ABL1 128w
Ruxolitinib CSF3R 252w
Table 2 Variant allele frequencies and BCR-ABL transcript levels 3 years apart for predicted pathogenic mutations. Outgrowth of a CSF3R-mutant clone during treatment with BCR-ABL1 tyrosine kinase inhibitors drives disease evolution from CML to CNL
Gene Variant COSMIC v92
FATHMM prediction Variant Allele Frequency
69 weeks 116 weeks 225 weeks
KMT2C/MLL3 S1860C Pathogenic (score 0.90) 50.62 48.92
CSF3R T618I Pathogenic (score 0.96) 11.58 41.09
CSF3R W818* Pathogenic (score 0.83) 10.22 40.26
TET2 R1167K Pathogenic (score 0.99) 2.86
ABL1 E255V (not annotated) 2.01 Not detected (targeted PCR)
ABL1 T3151 (not annotated) Detected (targeted PCR)
BCR-ABL1 2.50% (IS) 0.508% (IS) 0.000% (IS)
After 18 weeks on nilotinib, the patient presented with chest pain and was found to have pericarditis, atrial fibrillation, and severe thrombocytopenia (platelets at 11,000). The patient was ultimately started on imatinib at 400 mg/day but thrombocytopenia remained problematic. After 2 months, imatinib was reduced to 300 mg/day in an attempt to stabilize the patient’s ongoing thrombocytopenia. His platelets only slightly improved, however BCR-ABL1 transcripts decreased. The 400 mg/day dose was resumed when BCR-ABL1 rose from 0.68 to 2.74% (IS); however, subsequent ABL sequencing detected an imatinib and nilotinib-resistant E255V mutation [4], and the patient switched to dasatinib at 100 mg/day.
The leukemia responded well to dasatinib, though BCR-ABL1 transcript level plateaued above 0.1% (IS), the threshold for a major molecular response. ABL sequencing after 9 months of treatment detected a T315I mutation, which confers resistance to dasatinib, nilotinib, imatinib and bosutinib [5–11]. The patient was switched to ponatinib (30 mg/day) and his BCR-ABL1 transcript levels decreased steadily, falling below 0.1% (IS) after 3 months. The patient tolerated ponatinib well, with no thrombocytopenia. After 2 years on ponatinib, the (9;22) translocation was not detected by FISH in 200 cells scored for BCR (22Q11.2)/ABL (9Q34). Additionally, the BCR-ABL1 fusion gene was no longer detectable by PCR, 0.000% (IS). After 2.5 years, the dose of ponatinib was reduced to 15 mg/day.
Despite the disappearance of the Ph chromosome, the patient’s white blood cell and absolute neutrophil counts rose while on ponatinib, raising concerns about whether a second Ph-negative MPN could be emerging (Fig. 1). A 220 gene next generation sequencing panel was ordered and two CSF3R mutations, T618I and W818*, were identified at a variant allele frequency (VAF) of 41.1 and 40.3%, respectively. Predicted pathogenic variants were identified based on the COSMIC v92 (Catalogue of Somatic Mutations in Cancer) database. Retrospective analysis of an archived marrow sample revealed that the CSF3R mutations had been present for at least the past 3 years. Bone marrow from diagnosis was not available for retrospective next generation sequencing analyses. In total, six predicted-pathogenic variants were detected in the patient over the course of his treatment, including two CSF3R mutations (T618I and W818*), two ABL1 mutations (E255V and T315I), KMT2C/MLL3 (S1860C), and TET2 (R1167K) (Table 2).
Fig. 1 Emergence of a CSF3R-mutant, neutrophilic leukemia during targeted therapy for BCR-ABL1. Hematologic toxicity and the emergence of treatment-resistant clones shaped this CML patient’s clinical course. Ultimately, treatment with ponatinib successfully controlled the BCR-ABL1 clone, while another neutrophilic clone containing CSF3R mutations, but not BCR-ABL1, expanded
CSF3R mutations are a hallmark of chronic neutrophilic leukemia (CNL), a rare MPN defined by persistent mature neutrophilic leukocytosis. When the CSF3R variants were detected, the patient’s WBC was 22,800/mm3 with 83% neutrophils, within the range of WHO-defined CNL (11,000–126,000/mm3, median 39,000/mm3). The patient was started on ruxolitinib (5 mg twice daily), which demonstrated efficacy against CNL and CSF3R-mutant atypical CML in a recent clinical trial [12, 13]. With ruxolitinib, the patient’s WBC count decreased slightly and stabilized between 12,800-17,400/mm3, absolute neutrophils between 9700 and 14,300/mm3, platelets were stable at 124,000-155,000/mm3, hemoglobin at 15.3–16.6 g/dL, hematocrit at 46.6–51%. Ruxolitinib was increased to 7.5 mg twice daily after 7 months, which lowered his WBC (8900-13,000/mm3) and absolute neutrophil (6300-10,000/mm3) counts further. At 5.8 years post CML diagnosis and 3.5 years on ponatinib, a third FISH analysis was performed and the (9;22) translocation was still not detectable (200 nuclei).
Discussion and conclusions
This patient had difficulty tolerating tyrosine kinase inhibitors (TKIs), primarily due to hematologic toxicity. While thrombocytopenia is a known side effect of TKIs, the severity and protracted nature of the side effect in this instance suggests dysfunction in the residual BCR-ABL1 negative stem cells. In this case, the emergence of six predicted-pathogenetic variants over the five-year course of treatment suggests that the patient either had a markedly elevated mutational load prior to diagnosis—with different clones emerging in response to TKI selection—or a propensity to develop mutations beyond what is normally associated with aging.
The mutations in BCR-ABL1 and TET2 were present at similar variant allele frequencies at 69 weeks and lost during treatment with dasatinib and ponatinib, suggesting they were present in the same clone. Meanwhile, the CSF3R-mutant clone expanded during BCR-ABL1-directed therapy and is likely independent. Given that the increase in neutrophils began when the patient was switched from dasatinib to ponatinib, it is plausible that the expansion of this clone occurred during treatment with ponatinib specifically. It is known that CSF3R truncating mutations are sensitive to dasatinib [14], and that may have contributed to a delayed onset of this second MPN.
It is well established that selective pressure from TKIs allows for the outgrowth of BCR-ABL1 clones harboring point mutations in ABL1. However, this study suggests that the clearance of a BCR-ABL1 positive clone allowed for the outgrowth of a second, genetically distinct leukemia. It is interesting to note that two granulocytic leukemias arose in this patient, suggesting that either cell intrinsic or microenvironmental factors caused a specific predilection for malignancies of the granulocytic lineage. Germline mutations have not been accessed for this patient. This case describes the exceedingly rare co-occurrence of CML and CNL in the same individual and is an unusual example of clonal evolution under selective pressure from targeted therapy. These findings highlight that myeloid disease with complex clonal architecture is prone to molecular evolution. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Abbreviations
MPNsMyeloproliferative neoplasms
CMLChronic myeloid leukemia
CNLChronic neutrophilic leukemia
PhPhiladelphia
FISHChromosome, Fluorescent In Situ Hybridization
ISInternational scale
TKIsTyrosine kinase inhibitors
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Authors thank colleagues at Arizona Center for Cancer Care and Grande Ronde Hospital for collaboration on the care of the patient.
Authors’ contributions
DB and BJD treated the patient; SAC, TPB and JEM analyzed and/or interpreted the data; SAC and TPB wrote the paper. All authors reviewed and approved the manuscript.
Funding
SAC is supported by a fellowship from the National Cancer Institute, F32CA239422. JEM is supported by an American Society of Hematology Scholar Award, a Gilead Research Scholars Award, and American Cancer Society RSG-19-184-01-LIB. TPB is supported by KL2 TR002370–03 and K08 CA245224–01. BJD is supported by Howard Hughes Medical Institute and R01 CA065823–24.
Availability of data and materials
Data sharing requests should be sent to the corresponding author.
Ethics approval and consent to participate
The OHSU IRB determined that the proposed activity is not research involving human subjects. Access and use of protected health information complies with OHSU HIPAA policies for non-research activities.
Consent for publication
Not applicable. Data presented in this study has been de-identified and contains none of the 18 HIPPA individual identifiers.
Competing interests
B.J.D. potential competing interests–SAB: Aileron Therapeutics, ALLCRON, Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Baxalta (inactive), Monojul (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, Third Coast Therapeutics, GRAIL (inactive), CTI BioPharma (inactive); scientific founder: MolecularMD (inactive, acquired by ICON); board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; founder: VP Therapeutics; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana- Farber Cancer Institute (one Merck exclusive license). B.J.D. potential competing interests– consultant: Monojul, Patient True Talk; SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI Bio-Pharma (inactive); scientific founder and stock: MolecularMD; board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties: OHSU #606-Novartis exclusive license, OHSU #2573; Dana-Farber Cancer Institute #2063- Merck exclusive license. J.E.M. receives grant funding from the Gilead Research Scholars Program. The remaining authors declare no competing interests. | DASATINIB, IMATINIB MESYLATE, NILOTINIB, PONATINIB | DrugsGivenReaction | CC BY | 33516272 | 19,132,277 | 2021-01-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutrophil count increased'. | Outgrowth of a CSF3R-mutant clone drives a second myeloproliferative neoplasm in a chronic myeloid leukemia patient: a case report.
BACKGROUND
Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two myeloproliferative neoplasms with mutually exclusive diagnostic criteria. A hallmark of CML is the Philadelphia chromosome (Ph), which results in a BCR-ABL1 fusion gene and constitutive tyrosine kinase activity. CNL is a Ph-negative neoplasm and is defined in part by the presence of CSF3R mutations, which drive constative JAK/STAT signaling.
METHODS
Here, we report the exceedingly rare co-occurrence of two granulocytic myeloproliferative neoplasms in a 69-year old male patient. After an initial diagnosis of chronic myeloid leukemia, the patient's clinical course was shaped by hematologic toxicity, the emergence of treatment-resistant BCR-ABL1 clones, and the expansion of a CSF3R-mutant clone without ABL1 mutations under selective pressure from tyrosine kinase inhibitors. The emergence of the CSF3R-mutant, neutrophilic clone led to the diagnosis of CNL as a second myeloproliferative neoplasm in the same patient.
CONCLUSIONS
This is the first reported case of CNL arising subsequent to CML, which occurred under selective pressure from targeted therapy in a patient with complex clonal architecture. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Background
Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies in which a hematopoietic stem cell defect drives proliferation of mature myeloid cell lineages. Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two MPNs with mutually exclusive diagnostic criteria. A hallmark of CML is the presence of the Philadelphia (Ph) chromosome, which results from t (9;22) and separates CML from Ph-negative MPNs: essential thrombocythemia, primary myelofibrosis, polycythemia vera, chronic neutrophilic leukemia [1]. The BCR-ABL1 fusion gene results from t (9;22) and drives the proliferation of mature myeloid cells through constitutive tyrosine kinase activity [2, 3]. In this report, we describe a second rare MPN, chronic neutrophilic leukemia (CNL), arising after a CML patient achieved a complete molecular remission. This is the first reported case of CNL arising subsequent to CML.
Case presentation
A 69-year-old presented initially to his primary care provider with a progressive cough accompanied by weakness, fatigue, and abdominal distension. His white cell count was 113,900/mm3, hemoglobin was 11.8 g/dL, and platelet count was 325,000/mm3. A bone marrow biopsy showed a markedly hypercellular marrow (100%) with ~ 4% blasts, consistent with chronic phase CML. A 300 cell differential showed left-shifted myelopoiesis in which mid-range differentiated granulocytes—myelocytes, metamyelocytes with lesser amounts of promyelocytes—predominated over more differentiated forms. Myeloid and erythroid precursors were present in a 20:1 ratio. Auer rods were not observed. A Fluorescent In Situ Hybridization (FISH) assay confirmed a BCR-ABL1 translocation and cytogenetics revealed the Ph chromosome resulting from a (9;22) translocation. The major BCR-ABL1 transcript (p210) was 66.45% on the international scale (IS). The patient was started on 300 mg of nilotinib twice daily, which reduced his BCR-ABL1 to 0.403% (IS) in 18 weeks. However, the emergence of six new pathogenic mutations as well as hematologic toxicity of ABL1 inhibitors in this case made the treatment course complex (Tables 1, 2).
Table 1 Treatment strategy. The patient had difficulty tolerating TKIs due to hematologic toxicity (thrombocytopenia). Additionally, identification of three genetic variants triggered three treatment changes: imatinib and nilotinib-resistant BCR-ABL1 E255V, ponatinib-sensitive BCR-ABL1 T315I, ruxolitinib-sensitive CSF3R mutations. Dates initiated and discontinued are the number of weeks post-diagnosis of CML
Inhibitor Molecular Target Initiated Discontinued Reason Discontinued
Nilotinib BCR-ABL1 0w 28w Thrombocytopenia
Imatinib BCR-ABL1 33w 78w BCR-ABL1 p.E255V
Dasatinib BCR-ABL1 79w 118w BCR-ABL1 p.T315I
Ponatinib BCR-ABL1 128w
Ruxolitinib CSF3R 252w
Table 2 Variant allele frequencies and BCR-ABL transcript levels 3 years apart for predicted pathogenic mutations. Outgrowth of a CSF3R-mutant clone during treatment with BCR-ABL1 tyrosine kinase inhibitors drives disease evolution from CML to CNL
Gene Variant COSMIC v92
FATHMM prediction Variant Allele Frequency
69 weeks 116 weeks 225 weeks
KMT2C/MLL3 S1860C Pathogenic (score 0.90) 50.62 48.92
CSF3R T618I Pathogenic (score 0.96) 11.58 41.09
CSF3R W818* Pathogenic (score 0.83) 10.22 40.26
TET2 R1167K Pathogenic (score 0.99) 2.86
ABL1 E255V (not annotated) 2.01 Not detected (targeted PCR)
ABL1 T3151 (not annotated) Detected (targeted PCR)
BCR-ABL1 2.50% (IS) 0.508% (IS) 0.000% (IS)
After 18 weeks on nilotinib, the patient presented with chest pain and was found to have pericarditis, atrial fibrillation, and severe thrombocytopenia (platelets at 11,000). The patient was ultimately started on imatinib at 400 mg/day but thrombocytopenia remained problematic. After 2 months, imatinib was reduced to 300 mg/day in an attempt to stabilize the patient’s ongoing thrombocytopenia. His platelets only slightly improved, however BCR-ABL1 transcripts decreased. The 400 mg/day dose was resumed when BCR-ABL1 rose from 0.68 to 2.74% (IS); however, subsequent ABL sequencing detected an imatinib and nilotinib-resistant E255V mutation [4], and the patient switched to dasatinib at 100 mg/day.
The leukemia responded well to dasatinib, though BCR-ABL1 transcript level plateaued above 0.1% (IS), the threshold for a major molecular response. ABL sequencing after 9 months of treatment detected a T315I mutation, which confers resistance to dasatinib, nilotinib, imatinib and bosutinib [5–11]. The patient was switched to ponatinib (30 mg/day) and his BCR-ABL1 transcript levels decreased steadily, falling below 0.1% (IS) after 3 months. The patient tolerated ponatinib well, with no thrombocytopenia. After 2 years on ponatinib, the (9;22) translocation was not detected by FISH in 200 cells scored for BCR (22Q11.2)/ABL (9Q34). Additionally, the BCR-ABL1 fusion gene was no longer detectable by PCR, 0.000% (IS). After 2.5 years, the dose of ponatinib was reduced to 15 mg/day.
Despite the disappearance of the Ph chromosome, the patient’s white blood cell and absolute neutrophil counts rose while on ponatinib, raising concerns about whether a second Ph-negative MPN could be emerging (Fig. 1). A 220 gene next generation sequencing panel was ordered and two CSF3R mutations, T618I and W818*, were identified at a variant allele frequency (VAF) of 41.1 and 40.3%, respectively. Predicted pathogenic variants were identified based on the COSMIC v92 (Catalogue of Somatic Mutations in Cancer) database. Retrospective analysis of an archived marrow sample revealed that the CSF3R mutations had been present for at least the past 3 years. Bone marrow from diagnosis was not available for retrospective next generation sequencing analyses. In total, six predicted-pathogenic variants were detected in the patient over the course of his treatment, including two CSF3R mutations (T618I and W818*), two ABL1 mutations (E255V and T315I), KMT2C/MLL3 (S1860C), and TET2 (R1167K) (Table 2).
Fig. 1 Emergence of a CSF3R-mutant, neutrophilic leukemia during targeted therapy for BCR-ABL1. Hematologic toxicity and the emergence of treatment-resistant clones shaped this CML patient’s clinical course. Ultimately, treatment with ponatinib successfully controlled the BCR-ABL1 clone, while another neutrophilic clone containing CSF3R mutations, but not BCR-ABL1, expanded
CSF3R mutations are a hallmark of chronic neutrophilic leukemia (CNL), a rare MPN defined by persistent mature neutrophilic leukocytosis. When the CSF3R variants were detected, the patient’s WBC was 22,800/mm3 with 83% neutrophils, within the range of WHO-defined CNL (11,000–126,000/mm3, median 39,000/mm3). The patient was started on ruxolitinib (5 mg twice daily), which demonstrated efficacy against CNL and CSF3R-mutant atypical CML in a recent clinical trial [12, 13]. With ruxolitinib, the patient’s WBC count decreased slightly and stabilized between 12,800-17,400/mm3, absolute neutrophils between 9700 and 14,300/mm3, platelets were stable at 124,000-155,000/mm3, hemoglobin at 15.3–16.6 g/dL, hematocrit at 46.6–51%. Ruxolitinib was increased to 7.5 mg twice daily after 7 months, which lowered his WBC (8900-13,000/mm3) and absolute neutrophil (6300-10,000/mm3) counts further. At 5.8 years post CML diagnosis and 3.5 years on ponatinib, a third FISH analysis was performed and the (9;22) translocation was still not detectable (200 nuclei).
Discussion and conclusions
This patient had difficulty tolerating tyrosine kinase inhibitors (TKIs), primarily due to hematologic toxicity. While thrombocytopenia is a known side effect of TKIs, the severity and protracted nature of the side effect in this instance suggests dysfunction in the residual BCR-ABL1 negative stem cells. In this case, the emergence of six predicted-pathogenetic variants over the five-year course of treatment suggests that the patient either had a markedly elevated mutational load prior to diagnosis—with different clones emerging in response to TKI selection—or a propensity to develop mutations beyond what is normally associated with aging.
The mutations in BCR-ABL1 and TET2 were present at similar variant allele frequencies at 69 weeks and lost during treatment with dasatinib and ponatinib, suggesting they were present in the same clone. Meanwhile, the CSF3R-mutant clone expanded during BCR-ABL1-directed therapy and is likely independent. Given that the increase in neutrophils began when the patient was switched from dasatinib to ponatinib, it is plausible that the expansion of this clone occurred during treatment with ponatinib specifically. It is known that CSF3R truncating mutations are sensitive to dasatinib [14], and that may have contributed to a delayed onset of this second MPN.
It is well established that selective pressure from TKIs allows for the outgrowth of BCR-ABL1 clones harboring point mutations in ABL1. However, this study suggests that the clearance of a BCR-ABL1 positive clone allowed for the outgrowth of a second, genetically distinct leukemia. It is interesting to note that two granulocytic leukemias arose in this patient, suggesting that either cell intrinsic or microenvironmental factors caused a specific predilection for malignancies of the granulocytic lineage. Germline mutations have not been accessed for this patient. This case describes the exceedingly rare co-occurrence of CML and CNL in the same individual and is an unusual example of clonal evolution under selective pressure from targeted therapy. These findings highlight that myeloid disease with complex clonal architecture is prone to molecular evolution. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Abbreviations
MPNsMyeloproliferative neoplasms
CMLChronic myeloid leukemia
CNLChronic neutrophilic leukemia
PhPhiladelphia
FISHChromosome, Fluorescent In Situ Hybridization
ISInternational scale
TKIsTyrosine kinase inhibitors
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Authors thank colleagues at Arizona Center for Cancer Care and Grande Ronde Hospital for collaboration on the care of the patient.
Authors’ contributions
DB and BJD treated the patient; SAC, TPB and JEM analyzed and/or interpreted the data; SAC and TPB wrote the paper. All authors reviewed and approved the manuscript.
Funding
SAC is supported by a fellowship from the National Cancer Institute, F32CA239422. JEM is supported by an American Society of Hematology Scholar Award, a Gilead Research Scholars Award, and American Cancer Society RSG-19-184-01-LIB. TPB is supported by KL2 TR002370–03 and K08 CA245224–01. BJD is supported by Howard Hughes Medical Institute and R01 CA065823–24.
Availability of data and materials
Data sharing requests should be sent to the corresponding author.
Ethics approval and consent to participate
The OHSU IRB determined that the proposed activity is not research involving human subjects. Access and use of protected health information complies with OHSU HIPAA policies for non-research activities.
Consent for publication
Not applicable. Data presented in this study has been de-identified and contains none of the 18 HIPPA individual identifiers.
Competing interests
B.J.D. potential competing interests–SAB: Aileron Therapeutics, ALLCRON, Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Baxalta (inactive), Monojul (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, Third Coast Therapeutics, GRAIL (inactive), CTI BioPharma (inactive); scientific founder: MolecularMD (inactive, acquired by ICON); board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; founder: VP Therapeutics; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana- Farber Cancer Institute (one Merck exclusive license). B.J.D. potential competing interests– consultant: Monojul, Patient True Talk; SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI Bio-Pharma (inactive); scientific founder and stock: MolecularMD; board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties: OHSU #606-Novartis exclusive license, OHSU #2573; Dana-Farber Cancer Institute #2063- Merck exclusive license. J.E.M. receives grant funding from the Gilead Research Scholars Program. The remaining authors declare no competing interests. | PONATINIB | DrugsGivenReaction | CC BY | 33516272 | 19,168,698 | 2021-01-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutrophilia'. | Outgrowth of a CSF3R-mutant clone drives a second myeloproliferative neoplasm in a chronic myeloid leukemia patient: a case report.
BACKGROUND
Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two myeloproliferative neoplasms with mutually exclusive diagnostic criteria. A hallmark of CML is the Philadelphia chromosome (Ph), which results in a BCR-ABL1 fusion gene and constitutive tyrosine kinase activity. CNL is a Ph-negative neoplasm and is defined in part by the presence of CSF3R mutations, which drive constative JAK/STAT signaling.
METHODS
Here, we report the exceedingly rare co-occurrence of two granulocytic myeloproliferative neoplasms in a 69-year old male patient. After an initial diagnosis of chronic myeloid leukemia, the patient's clinical course was shaped by hematologic toxicity, the emergence of treatment-resistant BCR-ABL1 clones, and the expansion of a CSF3R-mutant clone without ABL1 mutations under selective pressure from tyrosine kinase inhibitors. The emergence of the CSF3R-mutant, neutrophilic clone led to the diagnosis of CNL as a second myeloproliferative neoplasm in the same patient.
CONCLUSIONS
This is the first reported case of CNL arising subsequent to CML, which occurred under selective pressure from targeted therapy in a patient with complex clonal architecture. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Background
Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies in which a hematopoietic stem cell defect drives proliferation of mature myeloid cell lineages. Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two MPNs with mutually exclusive diagnostic criteria. A hallmark of CML is the presence of the Philadelphia (Ph) chromosome, which results from t (9;22) and separates CML from Ph-negative MPNs: essential thrombocythemia, primary myelofibrosis, polycythemia vera, chronic neutrophilic leukemia [1]. The BCR-ABL1 fusion gene results from t (9;22) and drives the proliferation of mature myeloid cells through constitutive tyrosine kinase activity [2, 3]. In this report, we describe a second rare MPN, chronic neutrophilic leukemia (CNL), arising after a CML patient achieved a complete molecular remission. This is the first reported case of CNL arising subsequent to CML.
Case presentation
A 69-year-old presented initially to his primary care provider with a progressive cough accompanied by weakness, fatigue, and abdominal distension. His white cell count was 113,900/mm3, hemoglobin was 11.8 g/dL, and platelet count was 325,000/mm3. A bone marrow biopsy showed a markedly hypercellular marrow (100%) with ~ 4% blasts, consistent with chronic phase CML. A 300 cell differential showed left-shifted myelopoiesis in which mid-range differentiated granulocytes—myelocytes, metamyelocytes with lesser amounts of promyelocytes—predominated over more differentiated forms. Myeloid and erythroid precursors were present in a 20:1 ratio. Auer rods were not observed. A Fluorescent In Situ Hybridization (FISH) assay confirmed a BCR-ABL1 translocation and cytogenetics revealed the Ph chromosome resulting from a (9;22) translocation. The major BCR-ABL1 transcript (p210) was 66.45% on the international scale (IS). The patient was started on 300 mg of nilotinib twice daily, which reduced his BCR-ABL1 to 0.403% (IS) in 18 weeks. However, the emergence of six new pathogenic mutations as well as hematologic toxicity of ABL1 inhibitors in this case made the treatment course complex (Tables 1, 2).
Table 1 Treatment strategy. The patient had difficulty tolerating TKIs due to hematologic toxicity (thrombocytopenia). Additionally, identification of three genetic variants triggered three treatment changes: imatinib and nilotinib-resistant BCR-ABL1 E255V, ponatinib-sensitive BCR-ABL1 T315I, ruxolitinib-sensitive CSF3R mutations. Dates initiated and discontinued are the number of weeks post-diagnosis of CML
Inhibitor Molecular Target Initiated Discontinued Reason Discontinued
Nilotinib BCR-ABL1 0w 28w Thrombocytopenia
Imatinib BCR-ABL1 33w 78w BCR-ABL1 p.E255V
Dasatinib BCR-ABL1 79w 118w BCR-ABL1 p.T315I
Ponatinib BCR-ABL1 128w
Ruxolitinib CSF3R 252w
Table 2 Variant allele frequencies and BCR-ABL transcript levels 3 years apart for predicted pathogenic mutations. Outgrowth of a CSF3R-mutant clone during treatment with BCR-ABL1 tyrosine kinase inhibitors drives disease evolution from CML to CNL
Gene Variant COSMIC v92
FATHMM prediction Variant Allele Frequency
69 weeks 116 weeks 225 weeks
KMT2C/MLL3 S1860C Pathogenic (score 0.90) 50.62 48.92
CSF3R T618I Pathogenic (score 0.96) 11.58 41.09
CSF3R W818* Pathogenic (score 0.83) 10.22 40.26
TET2 R1167K Pathogenic (score 0.99) 2.86
ABL1 E255V (not annotated) 2.01 Not detected (targeted PCR)
ABL1 T3151 (not annotated) Detected (targeted PCR)
BCR-ABL1 2.50% (IS) 0.508% (IS) 0.000% (IS)
After 18 weeks on nilotinib, the patient presented with chest pain and was found to have pericarditis, atrial fibrillation, and severe thrombocytopenia (platelets at 11,000). The patient was ultimately started on imatinib at 400 mg/day but thrombocytopenia remained problematic. After 2 months, imatinib was reduced to 300 mg/day in an attempt to stabilize the patient’s ongoing thrombocytopenia. His platelets only slightly improved, however BCR-ABL1 transcripts decreased. The 400 mg/day dose was resumed when BCR-ABL1 rose from 0.68 to 2.74% (IS); however, subsequent ABL sequencing detected an imatinib and nilotinib-resistant E255V mutation [4], and the patient switched to dasatinib at 100 mg/day.
The leukemia responded well to dasatinib, though BCR-ABL1 transcript level plateaued above 0.1% (IS), the threshold for a major molecular response. ABL sequencing after 9 months of treatment detected a T315I mutation, which confers resistance to dasatinib, nilotinib, imatinib and bosutinib [5–11]. The patient was switched to ponatinib (30 mg/day) and his BCR-ABL1 transcript levels decreased steadily, falling below 0.1% (IS) after 3 months. The patient tolerated ponatinib well, with no thrombocytopenia. After 2 years on ponatinib, the (9;22) translocation was not detected by FISH in 200 cells scored for BCR (22Q11.2)/ABL (9Q34). Additionally, the BCR-ABL1 fusion gene was no longer detectable by PCR, 0.000% (IS). After 2.5 years, the dose of ponatinib was reduced to 15 mg/day.
Despite the disappearance of the Ph chromosome, the patient’s white blood cell and absolute neutrophil counts rose while on ponatinib, raising concerns about whether a second Ph-negative MPN could be emerging (Fig. 1). A 220 gene next generation sequencing panel was ordered and two CSF3R mutations, T618I and W818*, were identified at a variant allele frequency (VAF) of 41.1 and 40.3%, respectively. Predicted pathogenic variants were identified based on the COSMIC v92 (Catalogue of Somatic Mutations in Cancer) database. Retrospective analysis of an archived marrow sample revealed that the CSF3R mutations had been present for at least the past 3 years. Bone marrow from diagnosis was not available for retrospective next generation sequencing analyses. In total, six predicted-pathogenic variants were detected in the patient over the course of his treatment, including two CSF3R mutations (T618I and W818*), two ABL1 mutations (E255V and T315I), KMT2C/MLL3 (S1860C), and TET2 (R1167K) (Table 2).
Fig. 1 Emergence of a CSF3R-mutant, neutrophilic leukemia during targeted therapy for BCR-ABL1. Hematologic toxicity and the emergence of treatment-resistant clones shaped this CML patient’s clinical course. Ultimately, treatment with ponatinib successfully controlled the BCR-ABL1 clone, while another neutrophilic clone containing CSF3R mutations, but not BCR-ABL1, expanded
CSF3R mutations are a hallmark of chronic neutrophilic leukemia (CNL), a rare MPN defined by persistent mature neutrophilic leukocytosis. When the CSF3R variants were detected, the patient’s WBC was 22,800/mm3 with 83% neutrophils, within the range of WHO-defined CNL (11,000–126,000/mm3, median 39,000/mm3). The patient was started on ruxolitinib (5 mg twice daily), which demonstrated efficacy against CNL and CSF3R-mutant atypical CML in a recent clinical trial [12, 13]. With ruxolitinib, the patient’s WBC count decreased slightly and stabilized between 12,800-17,400/mm3, absolute neutrophils between 9700 and 14,300/mm3, platelets were stable at 124,000-155,000/mm3, hemoglobin at 15.3–16.6 g/dL, hematocrit at 46.6–51%. Ruxolitinib was increased to 7.5 mg twice daily after 7 months, which lowered his WBC (8900-13,000/mm3) and absolute neutrophil (6300-10,000/mm3) counts further. At 5.8 years post CML diagnosis and 3.5 years on ponatinib, a third FISH analysis was performed and the (9;22) translocation was still not detectable (200 nuclei).
Discussion and conclusions
This patient had difficulty tolerating tyrosine kinase inhibitors (TKIs), primarily due to hematologic toxicity. While thrombocytopenia is a known side effect of TKIs, the severity and protracted nature of the side effect in this instance suggests dysfunction in the residual BCR-ABL1 negative stem cells. In this case, the emergence of six predicted-pathogenetic variants over the five-year course of treatment suggests that the patient either had a markedly elevated mutational load prior to diagnosis—with different clones emerging in response to TKI selection—or a propensity to develop mutations beyond what is normally associated with aging.
The mutations in BCR-ABL1 and TET2 were present at similar variant allele frequencies at 69 weeks and lost during treatment with dasatinib and ponatinib, suggesting they were present in the same clone. Meanwhile, the CSF3R-mutant clone expanded during BCR-ABL1-directed therapy and is likely independent. Given that the increase in neutrophils began when the patient was switched from dasatinib to ponatinib, it is plausible that the expansion of this clone occurred during treatment with ponatinib specifically. It is known that CSF3R truncating mutations are sensitive to dasatinib [14], and that may have contributed to a delayed onset of this second MPN.
It is well established that selective pressure from TKIs allows for the outgrowth of BCR-ABL1 clones harboring point mutations in ABL1. However, this study suggests that the clearance of a BCR-ABL1 positive clone allowed for the outgrowth of a second, genetically distinct leukemia. It is interesting to note that two granulocytic leukemias arose in this patient, suggesting that either cell intrinsic or microenvironmental factors caused a specific predilection for malignancies of the granulocytic lineage. Germline mutations have not been accessed for this patient. This case describes the exceedingly rare co-occurrence of CML and CNL in the same individual and is an unusual example of clonal evolution under selective pressure from targeted therapy. These findings highlight that myeloid disease with complex clonal architecture is prone to molecular evolution. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Abbreviations
MPNsMyeloproliferative neoplasms
CMLChronic myeloid leukemia
CNLChronic neutrophilic leukemia
PhPhiladelphia
FISHChromosome, Fluorescent In Situ Hybridization
ISInternational scale
TKIsTyrosine kinase inhibitors
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Authors thank colleagues at Arizona Center for Cancer Care and Grande Ronde Hospital for collaboration on the care of the patient.
Authors’ contributions
DB and BJD treated the patient; SAC, TPB and JEM analyzed and/or interpreted the data; SAC and TPB wrote the paper. All authors reviewed and approved the manuscript.
Funding
SAC is supported by a fellowship from the National Cancer Institute, F32CA239422. JEM is supported by an American Society of Hematology Scholar Award, a Gilead Research Scholars Award, and American Cancer Society RSG-19-184-01-LIB. TPB is supported by KL2 TR002370–03 and K08 CA245224–01. BJD is supported by Howard Hughes Medical Institute and R01 CA065823–24.
Availability of data and materials
Data sharing requests should be sent to the corresponding author.
Ethics approval and consent to participate
The OHSU IRB determined that the proposed activity is not research involving human subjects. Access and use of protected health information complies with OHSU HIPAA policies for non-research activities.
Consent for publication
Not applicable. Data presented in this study has been de-identified and contains none of the 18 HIPPA individual identifiers.
Competing interests
B.J.D. potential competing interests–SAB: Aileron Therapeutics, ALLCRON, Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Baxalta (inactive), Monojul (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, Third Coast Therapeutics, GRAIL (inactive), CTI BioPharma (inactive); scientific founder: MolecularMD (inactive, acquired by ICON); board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; founder: VP Therapeutics; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana- Farber Cancer Institute (one Merck exclusive license). B.J.D. potential competing interests– consultant: Monojul, Patient True Talk; SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI Bio-Pharma (inactive); scientific founder and stock: MolecularMD; board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties: OHSU #606-Novartis exclusive license, OHSU #2573; Dana-Farber Cancer Institute #2063- Merck exclusive license. J.E.M. receives grant funding from the Gilead Research Scholars Program. The remaining authors declare no competing interests. | DASATINIB, IMATINIB MESYLATE, NILOTINIB, PONATINIB | DrugsGivenReaction | CC BY | 33516272 | 19,132,277 | 2021-01-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Outgrowth of a CSF3R-mutant clone drives a second myeloproliferative neoplasm in a chronic myeloid leukemia patient: a case report.
BACKGROUND
Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two myeloproliferative neoplasms with mutually exclusive diagnostic criteria. A hallmark of CML is the Philadelphia chromosome (Ph), which results in a BCR-ABL1 fusion gene and constitutive tyrosine kinase activity. CNL is a Ph-negative neoplasm and is defined in part by the presence of CSF3R mutations, which drive constative JAK/STAT signaling.
METHODS
Here, we report the exceedingly rare co-occurrence of two granulocytic myeloproliferative neoplasms in a 69-year old male patient. After an initial diagnosis of chronic myeloid leukemia, the patient's clinical course was shaped by hematologic toxicity, the emergence of treatment-resistant BCR-ABL1 clones, and the expansion of a CSF3R-mutant clone without ABL1 mutations under selective pressure from tyrosine kinase inhibitors. The emergence of the CSF3R-mutant, neutrophilic clone led to the diagnosis of CNL as a second myeloproliferative neoplasm in the same patient.
CONCLUSIONS
This is the first reported case of CNL arising subsequent to CML, which occurred under selective pressure from targeted therapy in a patient with complex clonal architecture. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Background
Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies in which a hematopoietic stem cell defect drives proliferation of mature myeloid cell lineages. Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two MPNs with mutually exclusive diagnostic criteria. A hallmark of CML is the presence of the Philadelphia (Ph) chromosome, which results from t (9;22) and separates CML from Ph-negative MPNs: essential thrombocythemia, primary myelofibrosis, polycythemia vera, chronic neutrophilic leukemia [1]. The BCR-ABL1 fusion gene results from t (9;22) and drives the proliferation of mature myeloid cells through constitutive tyrosine kinase activity [2, 3]. In this report, we describe a second rare MPN, chronic neutrophilic leukemia (CNL), arising after a CML patient achieved a complete molecular remission. This is the first reported case of CNL arising subsequent to CML.
Case presentation
A 69-year-old presented initially to his primary care provider with a progressive cough accompanied by weakness, fatigue, and abdominal distension. His white cell count was 113,900/mm3, hemoglobin was 11.8 g/dL, and platelet count was 325,000/mm3. A bone marrow biopsy showed a markedly hypercellular marrow (100%) with ~ 4% blasts, consistent with chronic phase CML. A 300 cell differential showed left-shifted myelopoiesis in which mid-range differentiated granulocytes—myelocytes, metamyelocytes with lesser amounts of promyelocytes—predominated over more differentiated forms. Myeloid and erythroid precursors were present in a 20:1 ratio. Auer rods were not observed. A Fluorescent In Situ Hybridization (FISH) assay confirmed a BCR-ABL1 translocation and cytogenetics revealed the Ph chromosome resulting from a (9;22) translocation. The major BCR-ABL1 transcript (p210) was 66.45% on the international scale (IS). The patient was started on 300 mg of nilotinib twice daily, which reduced his BCR-ABL1 to 0.403% (IS) in 18 weeks. However, the emergence of six new pathogenic mutations as well as hematologic toxicity of ABL1 inhibitors in this case made the treatment course complex (Tables 1, 2).
Table 1 Treatment strategy. The patient had difficulty tolerating TKIs due to hematologic toxicity (thrombocytopenia). Additionally, identification of three genetic variants triggered three treatment changes: imatinib and nilotinib-resistant BCR-ABL1 E255V, ponatinib-sensitive BCR-ABL1 T315I, ruxolitinib-sensitive CSF3R mutations. Dates initiated and discontinued are the number of weeks post-diagnosis of CML
Inhibitor Molecular Target Initiated Discontinued Reason Discontinued
Nilotinib BCR-ABL1 0w 28w Thrombocytopenia
Imatinib BCR-ABL1 33w 78w BCR-ABL1 p.E255V
Dasatinib BCR-ABL1 79w 118w BCR-ABL1 p.T315I
Ponatinib BCR-ABL1 128w
Ruxolitinib CSF3R 252w
Table 2 Variant allele frequencies and BCR-ABL transcript levels 3 years apart for predicted pathogenic mutations. Outgrowth of a CSF3R-mutant clone during treatment with BCR-ABL1 tyrosine kinase inhibitors drives disease evolution from CML to CNL
Gene Variant COSMIC v92
FATHMM prediction Variant Allele Frequency
69 weeks 116 weeks 225 weeks
KMT2C/MLL3 S1860C Pathogenic (score 0.90) 50.62 48.92
CSF3R T618I Pathogenic (score 0.96) 11.58 41.09
CSF3R W818* Pathogenic (score 0.83) 10.22 40.26
TET2 R1167K Pathogenic (score 0.99) 2.86
ABL1 E255V (not annotated) 2.01 Not detected (targeted PCR)
ABL1 T3151 (not annotated) Detected (targeted PCR)
BCR-ABL1 2.50% (IS) 0.508% (IS) 0.000% (IS)
After 18 weeks on nilotinib, the patient presented with chest pain and was found to have pericarditis, atrial fibrillation, and severe thrombocytopenia (platelets at 11,000). The patient was ultimately started on imatinib at 400 mg/day but thrombocytopenia remained problematic. After 2 months, imatinib was reduced to 300 mg/day in an attempt to stabilize the patient’s ongoing thrombocytopenia. His platelets only slightly improved, however BCR-ABL1 transcripts decreased. The 400 mg/day dose was resumed when BCR-ABL1 rose from 0.68 to 2.74% (IS); however, subsequent ABL sequencing detected an imatinib and nilotinib-resistant E255V mutation [4], and the patient switched to dasatinib at 100 mg/day.
The leukemia responded well to dasatinib, though BCR-ABL1 transcript level plateaued above 0.1% (IS), the threshold for a major molecular response. ABL sequencing after 9 months of treatment detected a T315I mutation, which confers resistance to dasatinib, nilotinib, imatinib and bosutinib [5–11]. The patient was switched to ponatinib (30 mg/day) and his BCR-ABL1 transcript levels decreased steadily, falling below 0.1% (IS) after 3 months. The patient tolerated ponatinib well, with no thrombocytopenia. After 2 years on ponatinib, the (9;22) translocation was not detected by FISH in 200 cells scored for BCR (22Q11.2)/ABL (9Q34). Additionally, the BCR-ABL1 fusion gene was no longer detectable by PCR, 0.000% (IS). After 2.5 years, the dose of ponatinib was reduced to 15 mg/day.
Despite the disappearance of the Ph chromosome, the patient’s white blood cell and absolute neutrophil counts rose while on ponatinib, raising concerns about whether a second Ph-negative MPN could be emerging (Fig. 1). A 220 gene next generation sequencing panel was ordered and two CSF3R mutations, T618I and W818*, were identified at a variant allele frequency (VAF) of 41.1 and 40.3%, respectively. Predicted pathogenic variants were identified based on the COSMIC v92 (Catalogue of Somatic Mutations in Cancer) database. Retrospective analysis of an archived marrow sample revealed that the CSF3R mutations had been present for at least the past 3 years. Bone marrow from diagnosis was not available for retrospective next generation sequencing analyses. In total, six predicted-pathogenic variants were detected in the patient over the course of his treatment, including two CSF3R mutations (T618I and W818*), two ABL1 mutations (E255V and T315I), KMT2C/MLL3 (S1860C), and TET2 (R1167K) (Table 2).
Fig. 1 Emergence of a CSF3R-mutant, neutrophilic leukemia during targeted therapy for BCR-ABL1. Hematologic toxicity and the emergence of treatment-resistant clones shaped this CML patient’s clinical course. Ultimately, treatment with ponatinib successfully controlled the BCR-ABL1 clone, while another neutrophilic clone containing CSF3R mutations, but not BCR-ABL1, expanded
CSF3R mutations are a hallmark of chronic neutrophilic leukemia (CNL), a rare MPN defined by persistent mature neutrophilic leukocytosis. When the CSF3R variants were detected, the patient’s WBC was 22,800/mm3 with 83% neutrophils, within the range of WHO-defined CNL (11,000–126,000/mm3, median 39,000/mm3). The patient was started on ruxolitinib (5 mg twice daily), which demonstrated efficacy against CNL and CSF3R-mutant atypical CML in a recent clinical trial [12, 13]. With ruxolitinib, the patient’s WBC count decreased slightly and stabilized between 12,800-17,400/mm3, absolute neutrophils between 9700 and 14,300/mm3, platelets were stable at 124,000-155,000/mm3, hemoglobin at 15.3–16.6 g/dL, hematocrit at 46.6–51%. Ruxolitinib was increased to 7.5 mg twice daily after 7 months, which lowered his WBC (8900-13,000/mm3) and absolute neutrophil (6300-10,000/mm3) counts further. At 5.8 years post CML diagnosis and 3.5 years on ponatinib, a third FISH analysis was performed and the (9;22) translocation was still not detectable (200 nuclei).
Discussion and conclusions
This patient had difficulty tolerating tyrosine kinase inhibitors (TKIs), primarily due to hematologic toxicity. While thrombocytopenia is a known side effect of TKIs, the severity and protracted nature of the side effect in this instance suggests dysfunction in the residual BCR-ABL1 negative stem cells. In this case, the emergence of six predicted-pathogenetic variants over the five-year course of treatment suggests that the patient either had a markedly elevated mutational load prior to diagnosis—with different clones emerging in response to TKI selection—or a propensity to develop mutations beyond what is normally associated with aging.
The mutations in BCR-ABL1 and TET2 were present at similar variant allele frequencies at 69 weeks and lost during treatment with dasatinib and ponatinib, suggesting they were present in the same clone. Meanwhile, the CSF3R-mutant clone expanded during BCR-ABL1-directed therapy and is likely independent. Given that the increase in neutrophils began when the patient was switched from dasatinib to ponatinib, it is plausible that the expansion of this clone occurred during treatment with ponatinib specifically. It is known that CSF3R truncating mutations are sensitive to dasatinib [14], and that may have contributed to a delayed onset of this second MPN.
It is well established that selective pressure from TKIs allows for the outgrowth of BCR-ABL1 clones harboring point mutations in ABL1. However, this study suggests that the clearance of a BCR-ABL1 positive clone allowed for the outgrowth of a second, genetically distinct leukemia. It is interesting to note that two granulocytic leukemias arose in this patient, suggesting that either cell intrinsic or microenvironmental factors caused a specific predilection for malignancies of the granulocytic lineage. Germline mutations have not been accessed for this patient. This case describes the exceedingly rare co-occurrence of CML and CNL in the same individual and is an unusual example of clonal evolution under selective pressure from targeted therapy. These findings highlight that myeloid disease with complex clonal architecture is prone to molecular evolution. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Abbreviations
MPNsMyeloproliferative neoplasms
CMLChronic myeloid leukemia
CNLChronic neutrophilic leukemia
PhPhiladelphia
FISHChromosome, Fluorescent In Situ Hybridization
ISInternational scale
TKIsTyrosine kinase inhibitors
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Authors thank colleagues at Arizona Center for Cancer Care and Grande Ronde Hospital for collaboration on the care of the patient.
Authors’ contributions
DB and BJD treated the patient; SAC, TPB and JEM analyzed and/or interpreted the data; SAC and TPB wrote the paper. All authors reviewed and approved the manuscript.
Funding
SAC is supported by a fellowship from the National Cancer Institute, F32CA239422. JEM is supported by an American Society of Hematology Scholar Award, a Gilead Research Scholars Award, and American Cancer Society RSG-19-184-01-LIB. TPB is supported by KL2 TR002370–03 and K08 CA245224–01. BJD is supported by Howard Hughes Medical Institute and R01 CA065823–24.
Availability of data and materials
Data sharing requests should be sent to the corresponding author.
Ethics approval and consent to participate
The OHSU IRB determined that the proposed activity is not research involving human subjects. Access and use of protected health information complies with OHSU HIPAA policies for non-research activities.
Consent for publication
Not applicable. Data presented in this study has been de-identified and contains none of the 18 HIPPA individual identifiers.
Competing interests
B.J.D. potential competing interests–SAB: Aileron Therapeutics, ALLCRON, Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Baxalta (inactive), Monojul (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, Third Coast Therapeutics, GRAIL (inactive), CTI BioPharma (inactive); scientific founder: MolecularMD (inactive, acquired by ICON); board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; founder: VP Therapeutics; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana- Farber Cancer Institute (one Merck exclusive license). B.J.D. potential competing interests– consultant: Monojul, Patient True Talk; SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI Bio-Pharma (inactive); scientific founder and stock: MolecularMD; board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties: OHSU #606-Novartis exclusive license, OHSU #2573; Dana-Farber Cancer Institute #2063- Merck exclusive license. J.E.M. receives grant funding from the Gilead Research Scholars Program. The remaining authors declare no competing interests. | PONATINIB | DrugsGivenReaction | CC BY | 33516272 | 19,168,698 | 2021-01-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'White blood cell count increased'. | Outgrowth of a CSF3R-mutant clone drives a second myeloproliferative neoplasm in a chronic myeloid leukemia patient: a case report.
BACKGROUND
Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two myeloproliferative neoplasms with mutually exclusive diagnostic criteria. A hallmark of CML is the Philadelphia chromosome (Ph), which results in a BCR-ABL1 fusion gene and constitutive tyrosine kinase activity. CNL is a Ph-negative neoplasm and is defined in part by the presence of CSF3R mutations, which drive constative JAK/STAT signaling.
METHODS
Here, we report the exceedingly rare co-occurrence of two granulocytic myeloproliferative neoplasms in a 69-year old male patient. After an initial diagnosis of chronic myeloid leukemia, the patient's clinical course was shaped by hematologic toxicity, the emergence of treatment-resistant BCR-ABL1 clones, and the expansion of a CSF3R-mutant clone without ABL1 mutations under selective pressure from tyrosine kinase inhibitors. The emergence of the CSF3R-mutant, neutrophilic clone led to the diagnosis of CNL as a second myeloproliferative neoplasm in the same patient.
CONCLUSIONS
This is the first reported case of CNL arising subsequent to CML, which occurred under selective pressure from targeted therapy in a patient with complex clonal architecture. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Background
Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies in which a hematopoietic stem cell defect drives proliferation of mature myeloid cell lineages. Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two MPNs with mutually exclusive diagnostic criteria. A hallmark of CML is the presence of the Philadelphia (Ph) chromosome, which results from t (9;22) and separates CML from Ph-negative MPNs: essential thrombocythemia, primary myelofibrosis, polycythemia vera, chronic neutrophilic leukemia [1]. The BCR-ABL1 fusion gene results from t (9;22) and drives the proliferation of mature myeloid cells through constitutive tyrosine kinase activity [2, 3]. In this report, we describe a second rare MPN, chronic neutrophilic leukemia (CNL), arising after a CML patient achieved a complete molecular remission. This is the first reported case of CNL arising subsequent to CML.
Case presentation
A 69-year-old presented initially to his primary care provider with a progressive cough accompanied by weakness, fatigue, and abdominal distension. His white cell count was 113,900/mm3, hemoglobin was 11.8 g/dL, and platelet count was 325,000/mm3. A bone marrow biopsy showed a markedly hypercellular marrow (100%) with ~ 4% blasts, consistent with chronic phase CML. A 300 cell differential showed left-shifted myelopoiesis in which mid-range differentiated granulocytes—myelocytes, metamyelocytes with lesser amounts of promyelocytes—predominated over more differentiated forms. Myeloid and erythroid precursors were present in a 20:1 ratio. Auer rods were not observed. A Fluorescent In Situ Hybridization (FISH) assay confirmed a BCR-ABL1 translocation and cytogenetics revealed the Ph chromosome resulting from a (9;22) translocation. The major BCR-ABL1 transcript (p210) was 66.45% on the international scale (IS). The patient was started on 300 mg of nilotinib twice daily, which reduced his BCR-ABL1 to 0.403% (IS) in 18 weeks. However, the emergence of six new pathogenic mutations as well as hematologic toxicity of ABL1 inhibitors in this case made the treatment course complex (Tables 1, 2).
Table 1 Treatment strategy. The patient had difficulty tolerating TKIs due to hematologic toxicity (thrombocytopenia). Additionally, identification of three genetic variants triggered three treatment changes: imatinib and nilotinib-resistant BCR-ABL1 E255V, ponatinib-sensitive BCR-ABL1 T315I, ruxolitinib-sensitive CSF3R mutations. Dates initiated and discontinued are the number of weeks post-diagnosis of CML
Inhibitor Molecular Target Initiated Discontinued Reason Discontinued
Nilotinib BCR-ABL1 0w 28w Thrombocytopenia
Imatinib BCR-ABL1 33w 78w BCR-ABL1 p.E255V
Dasatinib BCR-ABL1 79w 118w BCR-ABL1 p.T315I
Ponatinib BCR-ABL1 128w
Ruxolitinib CSF3R 252w
Table 2 Variant allele frequencies and BCR-ABL transcript levels 3 years apart for predicted pathogenic mutations. Outgrowth of a CSF3R-mutant clone during treatment with BCR-ABL1 tyrosine kinase inhibitors drives disease evolution from CML to CNL
Gene Variant COSMIC v92
FATHMM prediction Variant Allele Frequency
69 weeks 116 weeks 225 weeks
KMT2C/MLL3 S1860C Pathogenic (score 0.90) 50.62 48.92
CSF3R T618I Pathogenic (score 0.96) 11.58 41.09
CSF3R W818* Pathogenic (score 0.83) 10.22 40.26
TET2 R1167K Pathogenic (score 0.99) 2.86
ABL1 E255V (not annotated) 2.01 Not detected (targeted PCR)
ABL1 T3151 (not annotated) Detected (targeted PCR)
BCR-ABL1 2.50% (IS) 0.508% (IS) 0.000% (IS)
After 18 weeks on nilotinib, the patient presented with chest pain and was found to have pericarditis, atrial fibrillation, and severe thrombocytopenia (platelets at 11,000). The patient was ultimately started on imatinib at 400 mg/day but thrombocytopenia remained problematic. After 2 months, imatinib was reduced to 300 mg/day in an attempt to stabilize the patient’s ongoing thrombocytopenia. His platelets only slightly improved, however BCR-ABL1 transcripts decreased. The 400 mg/day dose was resumed when BCR-ABL1 rose from 0.68 to 2.74% (IS); however, subsequent ABL sequencing detected an imatinib and nilotinib-resistant E255V mutation [4], and the patient switched to dasatinib at 100 mg/day.
The leukemia responded well to dasatinib, though BCR-ABL1 transcript level plateaued above 0.1% (IS), the threshold for a major molecular response. ABL sequencing after 9 months of treatment detected a T315I mutation, which confers resistance to dasatinib, nilotinib, imatinib and bosutinib [5–11]. The patient was switched to ponatinib (30 mg/day) and his BCR-ABL1 transcript levels decreased steadily, falling below 0.1% (IS) after 3 months. The patient tolerated ponatinib well, with no thrombocytopenia. After 2 years on ponatinib, the (9;22) translocation was not detected by FISH in 200 cells scored for BCR (22Q11.2)/ABL (9Q34). Additionally, the BCR-ABL1 fusion gene was no longer detectable by PCR, 0.000% (IS). After 2.5 years, the dose of ponatinib was reduced to 15 mg/day.
Despite the disappearance of the Ph chromosome, the patient’s white blood cell and absolute neutrophil counts rose while on ponatinib, raising concerns about whether a second Ph-negative MPN could be emerging (Fig. 1). A 220 gene next generation sequencing panel was ordered and two CSF3R mutations, T618I and W818*, were identified at a variant allele frequency (VAF) of 41.1 and 40.3%, respectively. Predicted pathogenic variants were identified based on the COSMIC v92 (Catalogue of Somatic Mutations in Cancer) database. Retrospective analysis of an archived marrow sample revealed that the CSF3R mutations had been present for at least the past 3 years. Bone marrow from diagnosis was not available for retrospective next generation sequencing analyses. In total, six predicted-pathogenic variants were detected in the patient over the course of his treatment, including two CSF3R mutations (T618I and W818*), two ABL1 mutations (E255V and T315I), KMT2C/MLL3 (S1860C), and TET2 (R1167K) (Table 2).
Fig. 1 Emergence of a CSF3R-mutant, neutrophilic leukemia during targeted therapy for BCR-ABL1. Hematologic toxicity and the emergence of treatment-resistant clones shaped this CML patient’s clinical course. Ultimately, treatment with ponatinib successfully controlled the BCR-ABL1 clone, while another neutrophilic clone containing CSF3R mutations, but not BCR-ABL1, expanded
CSF3R mutations are a hallmark of chronic neutrophilic leukemia (CNL), a rare MPN defined by persistent mature neutrophilic leukocytosis. When the CSF3R variants were detected, the patient’s WBC was 22,800/mm3 with 83% neutrophils, within the range of WHO-defined CNL (11,000–126,000/mm3, median 39,000/mm3). The patient was started on ruxolitinib (5 mg twice daily), which demonstrated efficacy against CNL and CSF3R-mutant atypical CML in a recent clinical trial [12, 13]. With ruxolitinib, the patient’s WBC count decreased slightly and stabilized between 12,800-17,400/mm3, absolute neutrophils between 9700 and 14,300/mm3, platelets were stable at 124,000-155,000/mm3, hemoglobin at 15.3–16.6 g/dL, hematocrit at 46.6–51%. Ruxolitinib was increased to 7.5 mg twice daily after 7 months, which lowered his WBC (8900-13,000/mm3) and absolute neutrophil (6300-10,000/mm3) counts further. At 5.8 years post CML diagnosis and 3.5 years on ponatinib, a third FISH analysis was performed and the (9;22) translocation was still not detectable (200 nuclei).
Discussion and conclusions
This patient had difficulty tolerating tyrosine kinase inhibitors (TKIs), primarily due to hematologic toxicity. While thrombocytopenia is a known side effect of TKIs, the severity and protracted nature of the side effect in this instance suggests dysfunction in the residual BCR-ABL1 negative stem cells. In this case, the emergence of six predicted-pathogenetic variants over the five-year course of treatment suggests that the patient either had a markedly elevated mutational load prior to diagnosis—with different clones emerging in response to TKI selection—or a propensity to develop mutations beyond what is normally associated with aging.
The mutations in BCR-ABL1 and TET2 were present at similar variant allele frequencies at 69 weeks and lost during treatment with dasatinib and ponatinib, suggesting they were present in the same clone. Meanwhile, the CSF3R-mutant clone expanded during BCR-ABL1-directed therapy and is likely independent. Given that the increase in neutrophils began when the patient was switched from dasatinib to ponatinib, it is plausible that the expansion of this clone occurred during treatment with ponatinib specifically. It is known that CSF3R truncating mutations are sensitive to dasatinib [14], and that may have contributed to a delayed onset of this second MPN.
It is well established that selective pressure from TKIs allows for the outgrowth of BCR-ABL1 clones harboring point mutations in ABL1. However, this study suggests that the clearance of a BCR-ABL1 positive clone allowed for the outgrowth of a second, genetically distinct leukemia. It is interesting to note that two granulocytic leukemias arose in this patient, suggesting that either cell intrinsic or microenvironmental factors caused a specific predilection for malignancies of the granulocytic lineage. Germline mutations have not been accessed for this patient. This case describes the exceedingly rare co-occurrence of CML and CNL in the same individual and is an unusual example of clonal evolution under selective pressure from targeted therapy. These findings highlight that myeloid disease with complex clonal architecture is prone to molecular evolution. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Abbreviations
MPNsMyeloproliferative neoplasms
CMLChronic myeloid leukemia
CNLChronic neutrophilic leukemia
PhPhiladelphia
FISHChromosome, Fluorescent In Situ Hybridization
ISInternational scale
TKIsTyrosine kinase inhibitors
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Authors thank colleagues at Arizona Center for Cancer Care and Grande Ronde Hospital for collaboration on the care of the patient.
Authors’ contributions
DB and BJD treated the patient; SAC, TPB and JEM analyzed and/or interpreted the data; SAC and TPB wrote the paper. All authors reviewed and approved the manuscript.
Funding
SAC is supported by a fellowship from the National Cancer Institute, F32CA239422. JEM is supported by an American Society of Hematology Scholar Award, a Gilead Research Scholars Award, and American Cancer Society RSG-19-184-01-LIB. TPB is supported by KL2 TR002370–03 and K08 CA245224–01. BJD is supported by Howard Hughes Medical Institute and R01 CA065823–24.
Availability of data and materials
Data sharing requests should be sent to the corresponding author.
Ethics approval and consent to participate
The OHSU IRB determined that the proposed activity is not research involving human subjects. Access and use of protected health information complies with OHSU HIPAA policies for non-research activities.
Consent for publication
Not applicable. Data presented in this study has been de-identified and contains none of the 18 HIPPA individual identifiers.
Competing interests
B.J.D. potential competing interests–SAB: Aileron Therapeutics, ALLCRON, Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Baxalta (inactive), Monojul (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, Third Coast Therapeutics, GRAIL (inactive), CTI BioPharma (inactive); scientific founder: MolecularMD (inactive, acquired by ICON); board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; founder: VP Therapeutics; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana- Farber Cancer Institute (one Merck exclusive license). B.J.D. potential competing interests– consultant: Monojul, Patient True Talk; SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI Bio-Pharma (inactive); scientific founder and stock: MolecularMD; board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties: OHSU #606-Novartis exclusive license, OHSU #2573; Dana-Farber Cancer Institute #2063- Merck exclusive license. J.E.M. receives grant funding from the Gilead Research Scholars Program. The remaining authors declare no competing interests. | PONATINIB | DrugsGivenReaction | CC BY | 33516272 | 19,168,698 | 2021-01-30 |
What was the outcome of reaction 'Myeloproliferative neoplasm'? | Outgrowth of a CSF3R-mutant clone drives a second myeloproliferative neoplasm in a chronic myeloid leukemia patient: a case report.
BACKGROUND
Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two myeloproliferative neoplasms with mutually exclusive diagnostic criteria. A hallmark of CML is the Philadelphia chromosome (Ph), which results in a BCR-ABL1 fusion gene and constitutive tyrosine kinase activity. CNL is a Ph-negative neoplasm and is defined in part by the presence of CSF3R mutations, which drive constative JAK/STAT signaling.
METHODS
Here, we report the exceedingly rare co-occurrence of two granulocytic myeloproliferative neoplasms in a 69-year old male patient. After an initial diagnosis of chronic myeloid leukemia, the patient's clinical course was shaped by hematologic toxicity, the emergence of treatment-resistant BCR-ABL1 clones, and the expansion of a CSF3R-mutant clone without ABL1 mutations under selective pressure from tyrosine kinase inhibitors. The emergence of the CSF3R-mutant, neutrophilic clone led to the diagnosis of CNL as a second myeloproliferative neoplasm in the same patient.
CONCLUSIONS
This is the first reported case of CNL arising subsequent to CML, which occurred under selective pressure from targeted therapy in a patient with complex clonal architecture. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Background
Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies in which a hematopoietic stem cell defect drives proliferation of mature myeloid cell lineages. Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two MPNs with mutually exclusive diagnostic criteria. A hallmark of CML is the presence of the Philadelphia (Ph) chromosome, which results from t (9;22) and separates CML from Ph-negative MPNs: essential thrombocythemia, primary myelofibrosis, polycythemia vera, chronic neutrophilic leukemia [1]. The BCR-ABL1 fusion gene results from t (9;22) and drives the proliferation of mature myeloid cells through constitutive tyrosine kinase activity [2, 3]. In this report, we describe a second rare MPN, chronic neutrophilic leukemia (CNL), arising after a CML patient achieved a complete molecular remission. This is the first reported case of CNL arising subsequent to CML.
Case presentation
A 69-year-old presented initially to his primary care provider with a progressive cough accompanied by weakness, fatigue, and abdominal distension. His white cell count was 113,900/mm3, hemoglobin was 11.8 g/dL, and platelet count was 325,000/mm3. A bone marrow biopsy showed a markedly hypercellular marrow (100%) with ~ 4% blasts, consistent with chronic phase CML. A 300 cell differential showed left-shifted myelopoiesis in which mid-range differentiated granulocytes—myelocytes, metamyelocytes with lesser amounts of promyelocytes—predominated over more differentiated forms. Myeloid and erythroid precursors were present in a 20:1 ratio. Auer rods were not observed. A Fluorescent In Situ Hybridization (FISH) assay confirmed a BCR-ABL1 translocation and cytogenetics revealed the Ph chromosome resulting from a (9;22) translocation. The major BCR-ABL1 transcript (p210) was 66.45% on the international scale (IS). The patient was started on 300 mg of nilotinib twice daily, which reduced his BCR-ABL1 to 0.403% (IS) in 18 weeks. However, the emergence of six new pathogenic mutations as well as hematologic toxicity of ABL1 inhibitors in this case made the treatment course complex (Tables 1, 2).
Table 1 Treatment strategy. The patient had difficulty tolerating TKIs due to hematologic toxicity (thrombocytopenia). Additionally, identification of three genetic variants triggered three treatment changes: imatinib and nilotinib-resistant BCR-ABL1 E255V, ponatinib-sensitive BCR-ABL1 T315I, ruxolitinib-sensitive CSF3R mutations. Dates initiated and discontinued are the number of weeks post-diagnosis of CML
Inhibitor Molecular Target Initiated Discontinued Reason Discontinued
Nilotinib BCR-ABL1 0w 28w Thrombocytopenia
Imatinib BCR-ABL1 33w 78w BCR-ABL1 p.E255V
Dasatinib BCR-ABL1 79w 118w BCR-ABL1 p.T315I
Ponatinib BCR-ABL1 128w
Ruxolitinib CSF3R 252w
Table 2 Variant allele frequencies and BCR-ABL transcript levels 3 years apart for predicted pathogenic mutations. Outgrowth of a CSF3R-mutant clone during treatment with BCR-ABL1 tyrosine kinase inhibitors drives disease evolution from CML to CNL
Gene Variant COSMIC v92
FATHMM prediction Variant Allele Frequency
69 weeks 116 weeks 225 weeks
KMT2C/MLL3 S1860C Pathogenic (score 0.90) 50.62 48.92
CSF3R T618I Pathogenic (score 0.96) 11.58 41.09
CSF3R W818* Pathogenic (score 0.83) 10.22 40.26
TET2 R1167K Pathogenic (score 0.99) 2.86
ABL1 E255V (not annotated) 2.01 Not detected (targeted PCR)
ABL1 T3151 (not annotated) Detected (targeted PCR)
BCR-ABL1 2.50% (IS) 0.508% (IS) 0.000% (IS)
After 18 weeks on nilotinib, the patient presented with chest pain and was found to have pericarditis, atrial fibrillation, and severe thrombocytopenia (platelets at 11,000). The patient was ultimately started on imatinib at 400 mg/day but thrombocytopenia remained problematic. After 2 months, imatinib was reduced to 300 mg/day in an attempt to stabilize the patient’s ongoing thrombocytopenia. His platelets only slightly improved, however BCR-ABL1 transcripts decreased. The 400 mg/day dose was resumed when BCR-ABL1 rose from 0.68 to 2.74% (IS); however, subsequent ABL sequencing detected an imatinib and nilotinib-resistant E255V mutation [4], and the patient switched to dasatinib at 100 mg/day.
The leukemia responded well to dasatinib, though BCR-ABL1 transcript level plateaued above 0.1% (IS), the threshold for a major molecular response. ABL sequencing after 9 months of treatment detected a T315I mutation, which confers resistance to dasatinib, nilotinib, imatinib and bosutinib [5–11]. The patient was switched to ponatinib (30 mg/day) and his BCR-ABL1 transcript levels decreased steadily, falling below 0.1% (IS) after 3 months. The patient tolerated ponatinib well, with no thrombocytopenia. After 2 years on ponatinib, the (9;22) translocation was not detected by FISH in 200 cells scored for BCR (22Q11.2)/ABL (9Q34). Additionally, the BCR-ABL1 fusion gene was no longer detectable by PCR, 0.000% (IS). After 2.5 years, the dose of ponatinib was reduced to 15 mg/day.
Despite the disappearance of the Ph chromosome, the patient’s white blood cell and absolute neutrophil counts rose while on ponatinib, raising concerns about whether a second Ph-negative MPN could be emerging (Fig. 1). A 220 gene next generation sequencing panel was ordered and two CSF3R mutations, T618I and W818*, were identified at a variant allele frequency (VAF) of 41.1 and 40.3%, respectively. Predicted pathogenic variants were identified based on the COSMIC v92 (Catalogue of Somatic Mutations in Cancer) database. Retrospective analysis of an archived marrow sample revealed that the CSF3R mutations had been present for at least the past 3 years. Bone marrow from diagnosis was not available for retrospective next generation sequencing analyses. In total, six predicted-pathogenic variants were detected in the patient over the course of his treatment, including two CSF3R mutations (T618I and W818*), two ABL1 mutations (E255V and T315I), KMT2C/MLL3 (S1860C), and TET2 (R1167K) (Table 2).
Fig. 1 Emergence of a CSF3R-mutant, neutrophilic leukemia during targeted therapy for BCR-ABL1. Hematologic toxicity and the emergence of treatment-resistant clones shaped this CML patient’s clinical course. Ultimately, treatment with ponatinib successfully controlled the BCR-ABL1 clone, while another neutrophilic clone containing CSF3R mutations, but not BCR-ABL1, expanded
CSF3R mutations are a hallmark of chronic neutrophilic leukemia (CNL), a rare MPN defined by persistent mature neutrophilic leukocytosis. When the CSF3R variants were detected, the patient’s WBC was 22,800/mm3 with 83% neutrophils, within the range of WHO-defined CNL (11,000–126,000/mm3, median 39,000/mm3). The patient was started on ruxolitinib (5 mg twice daily), which demonstrated efficacy against CNL and CSF3R-mutant atypical CML in a recent clinical trial [12, 13]. With ruxolitinib, the patient’s WBC count decreased slightly and stabilized between 12,800-17,400/mm3, absolute neutrophils between 9700 and 14,300/mm3, platelets were stable at 124,000-155,000/mm3, hemoglobin at 15.3–16.6 g/dL, hematocrit at 46.6–51%. Ruxolitinib was increased to 7.5 mg twice daily after 7 months, which lowered his WBC (8900-13,000/mm3) and absolute neutrophil (6300-10,000/mm3) counts further. At 5.8 years post CML diagnosis and 3.5 years on ponatinib, a third FISH analysis was performed and the (9;22) translocation was still not detectable (200 nuclei).
Discussion and conclusions
This patient had difficulty tolerating tyrosine kinase inhibitors (TKIs), primarily due to hematologic toxicity. While thrombocytopenia is a known side effect of TKIs, the severity and protracted nature of the side effect in this instance suggests dysfunction in the residual BCR-ABL1 negative stem cells. In this case, the emergence of six predicted-pathogenetic variants over the five-year course of treatment suggests that the patient either had a markedly elevated mutational load prior to diagnosis—with different clones emerging in response to TKI selection—or a propensity to develop mutations beyond what is normally associated with aging.
The mutations in BCR-ABL1 and TET2 were present at similar variant allele frequencies at 69 weeks and lost during treatment with dasatinib and ponatinib, suggesting they were present in the same clone. Meanwhile, the CSF3R-mutant clone expanded during BCR-ABL1-directed therapy and is likely independent. Given that the increase in neutrophils began when the patient was switched from dasatinib to ponatinib, it is plausible that the expansion of this clone occurred during treatment with ponatinib specifically. It is known that CSF3R truncating mutations are sensitive to dasatinib [14], and that may have contributed to a delayed onset of this second MPN.
It is well established that selective pressure from TKIs allows for the outgrowth of BCR-ABL1 clones harboring point mutations in ABL1. However, this study suggests that the clearance of a BCR-ABL1 positive clone allowed for the outgrowth of a second, genetically distinct leukemia. It is interesting to note that two granulocytic leukemias arose in this patient, suggesting that either cell intrinsic or microenvironmental factors caused a specific predilection for malignancies of the granulocytic lineage. Germline mutations have not been accessed for this patient. This case describes the exceedingly rare co-occurrence of CML and CNL in the same individual and is an unusual example of clonal evolution under selective pressure from targeted therapy. These findings highlight that myeloid disease with complex clonal architecture is prone to molecular evolution. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Abbreviations
MPNsMyeloproliferative neoplasms
CMLChronic myeloid leukemia
CNLChronic neutrophilic leukemia
PhPhiladelphia
FISHChromosome, Fluorescent In Situ Hybridization
ISInternational scale
TKIsTyrosine kinase inhibitors
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Authors thank colleagues at Arizona Center for Cancer Care and Grande Ronde Hospital for collaboration on the care of the patient.
Authors’ contributions
DB and BJD treated the patient; SAC, TPB and JEM analyzed and/or interpreted the data; SAC and TPB wrote the paper. All authors reviewed and approved the manuscript.
Funding
SAC is supported by a fellowship from the National Cancer Institute, F32CA239422. JEM is supported by an American Society of Hematology Scholar Award, a Gilead Research Scholars Award, and American Cancer Society RSG-19-184-01-LIB. TPB is supported by KL2 TR002370–03 and K08 CA245224–01. BJD is supported by Howard Hughes Medical Institute and R01 CA065823–24.
Availability of data and materials
Data sharing requests should be sent to the corresponding author.
Ethics approval and consent to participate
The OHSU IRB determined that the proposed activity is not research involving human subjects. Access and use of protected health information complies with OHSU HIPAA policies for non-research activities.
Consent for publication
Not applicable. Data presented in this study has been de-identified and contains none of the 18 HIPPA individual identifiers.
Competing interests
B.J.D. potential competing interests–SAB: Aileron Therapeutics, ALLCRON, Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Baxalta (inactive), Monojul (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, Third Coast Therapeutics, GRAIL (inactive), CTI BioPharma (inactive); scientific founder: MolecularMD (inactive, acquired by ICON); board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; founder: VP Therapeutics; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana- Farber Cancer Institute (one Merck exclusive license). B.J.D. potential competing interests– consultant: Monojul, Patient True Talk; SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI Bio-Pharma (inactive); scientific founder and stock: MolecularMD; board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties: OHSU #606-Novartis exclusive license, OHSU #2573; Dana-Farber Cancer Institute #2063- Merck exclusive license. J.E.M. receives grant funding from the Gilead Research Scholars Program. The remaining authors declare no competing interests. | Recovering | ReactionOutcome | CC BY | 33516272 | 19,132,277 | 2021-01-30 |
What was the outcome of reaction 'Neutrophilia'? | Outgrowth of a CSF3R-mutant clone drives a second myeloproliferative neoplasm in a chronic myeloid leukemia patient: a case report.
BACKGROUND
Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two myeloproliferative neoplasms with mutually exclusive diagnostic criteria. A hallmark of CML is the Philadelphia chromosome (Ph), which results in a BCR-ABL1 fusion gene and constitutive tyrosine kinase activity. CNL is a Ph-negative neoplasm and is defined in part by the presence of CSF3R mutations, which drive constative JAK/STAT signaling.
METHODS
Here, we report the exceedingly rare co-occurrence of two granulocytic myeloproliferative neoplasms in a 69-year old male patient. After an initial diagnosis of chronic myeloid leukemia, the patient's clinical course was shaped by hematologic toxicity, the emergence of treatment-resistant BCR-ABL1 clones, and the expansion of a CSF3R-mutant clone without ABL1 mutations under selective pressure from tyrosine kinase inhibitors. The emergence of the CSF3R-mutant, neutrophilic clone led to the diagnosis of CNL as a second myeloproliferative neoplasm in the same patient.
CONCLUSIONS
This is the first reported case of CNL arising subsequent to CML, which occurred under selective pressure from targeted therapy in a patient with complex clonal architecture. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Background
Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies in which a hematopoietic stem cell defect drives proliferation of mature myeloid cell lineages. Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two MPNs with mutually exclusive diagnostic criteria. A hallmark of CML is the presence of the Philadelphia (Ph) chromosome, which results from t (9;22) and separates CML from Ph-negative MPNs: essential thrombocythemia, primary myelofibrosis, polycythemia vera, chronic neutrophilic leukemia [1]. The BCR-ABL1 fusion gene results from t (9;22) and drives the proliferation of mature myeloid cells through constitutive tyrosine kinase activity [2, 3]. In this report, we describe a second rare MPN, chronic neutrophilic leukemia (CNL), arising after a CML patient achieved a complete molecular remission. This is the first reported case of CNL arising subsequent to CML.
Case presentation
A 69-year-old presented initially to his primary care provider with a progressive cough accompanied by weakness, fatigue, and abdominal distension. His white cell count was 113,900/mm3, hemoglobin was 11.8 g/dL, and platelet count was 325,000/mm3. A bone marrow biopsy showed a markedly hypercellular marrow (100%) with ~ 4% blasts, consistent with chronic phase CML. A 300 cell differential showed left-shifted myelopoiesis in which mid-range differentiated granulocytes—myelocytes, metamyelocytes with lesser amounts of promyelocytes—predominated over more differentiated forms. Myeloid and erythroid precursors were present in a 20:1 ratio. Auer rods were not observed. A Fluorescent In Situ Hybridization (FISH) assay confirmed a BCR-ABL1 translocation and cytogenetics revealed the Ph chromosome resulting from a (9;22) translocation. The major BCR-ABL1 transcript (p210) was 66.45% on the international scale (IS). The patient was started on 300 mg of nilotinib twice daily, which reduced his BCR-ABL1 to 0.403% (IS) in 18 weeks. However, the emergence of six new pathogenic mutations as well as hematologic toxicity of ABL1 inhibitors in this case made the treatment course complex (Tables 1, 2).
Table 1 Treatment strategy. The patient had difficulty tolerating TKIs due to hematologic toxicity (thrombocytopenia). Additionally, identification of three genetic variants triggered three treatment changes: imatinib and nilotinib-resistant BCR-ABL1 E255V, ponatinib-sensitive BCR-ABL1 T315I, ruxolitinib-sensitive CSF3R mutations. Dates initiated and discontinued are the number of weeks post-diagnosis of CML
Inhibitor Molecular Target Initiated Discontinued Reason Discontinued
Nilotinib BCR-ABL1 0w 28w Thrombocytopenia
Imatinib BCR-ABL1 33w 78w BCR-ABL1 p.E255V
Dasatinib BCR-ABL1 79w 118w BCR-ABL1 p.T315I
Ponatinib BCR-ABL1 128w
Ruxolitinib CSF3R 252w
Table 2 Variant allele frequencies and BCR-ABL transcript levels 3 years apart for predicted pathogenic mutations. Outgrowth of a CSF3R-mutant clone during treatment with BCR-ABL1 tyrosine kinase inhibitors drives disease evolution from CML to CNL
Gene Variant COSMIC v92
FATHMM prediction Variant Allele Frequency
69 weeks 116 weeks 225 weeks
KMT2C/MLL3 S1860C Pathogenic (score 0.90) 50.62 48.92
CSF3R T618I Pathogenic (score 0.96) 11.58 41.09
CSF3R W818* Pathogenic (score 0.83) 10.22 40.26
TET2 R1167K Pathogenic (score 0.99) 2.86
ABL1 E255V (not annotated) 2.01 Not detected (targeted PCR)
ABL1 T3151 (not annotated) Detected (targeted PCR)
BCR-ABL1 2.50% (IS) 0.508% (IS) 0.000% (IS)
After 18 weeks on nilotinib, the patient presented with chest pain and was found to have pericarditis, atrial fibrillation, and severe thrombocytopenia (platelets at 11,000). The patient was ultimately started on imatinib at 400 mg/day but thrombocytopenia remained problematic. After 2 months, imatinib was reduced to 300 mg/day in an attempt to stabilize the patient’s ongoing thrombocytopenia. His platelets only slightly improved, however BCR-ABL1 transcripts decreased. The 400 mg/day dose was resumed when BCR-ABL1 rose from 0.68 to 2.74% (IS); however, subsequent ABL sequencing detected an imatinib and nilotinib-resistant E255V mutation [4], and the patient switched to dasatinib at 100 mg/day.
The leukemia responded well to dasatinib, though BCR-ABL1 transcript level plateaued above 0.1% (IS), the threshold for a major molecular response. ABL sequencing after 9 months of treatment detected a T315I mutation, which confers resistance to dasatinib, nilotinib, imatinib and bosutinib [5–11]. The patient was switched to ponatinib (30 mg/day) and his BCR-ABL1 transcript levels decreased steadily, falling below 0.1% (IS) after 3 months. The patient tolerated ponatinib well, with no thrombocytopenia. After 2 years on ponatinib, the (9;22) translocation was not detected by FISH in 200 cells scored for BCR (22Q11.2)/ABL (9Q34). Additionally, the BCR-ABL1 fusion gene was no longer detectable by PCR, 0.000% (IS). After 2.5 years, the dose of ponatinib was reduced to 15 mg/day.
Despite the disappearance of the Ph chromosome, the patient’s white blood cell and absolute neutrophil counts rose while on ponatinib, raising concerns about whether a second Ph-negative MPN could be emerging (Fig. 1). A 220 gene next generation sequencing panel was ordered and two CSF3R mutations, T618I and W818*, were identified at a variant allele frequency (VAF) of 41.1 and 40.3%, respectively. Predicted pathogenic variants were identified based on the COSMIC v92 (Catalogue of Somatic Mutations in Cancer) database. Retrospective analysis of an archived marrow sample revealed that the CSF3R mutations had been present for at least the past 3 years. Bone marrow from diagnosis was not available for retrospective next generation sequencing analyses. In total, six predicted-pathogenic variants were detected in the patient over the course of his treatment, including two CSF3R mutations (T618I and W818*), two ABL1 mutations (E255V and T315I), KMT2C/MLL3 (S1860C), and TET2 (R1167K) (Table 2).
Fig. 1 Emergence of a CSF3R-mutant, neutrophilic leukemia during targeted therapy for BCR-ABL1. Hematologic toxicity and the emergence of treatment-resistant clones shaped this CML patient’s clinical course. Ultimately, treatment with ponatinib successfully controlled the BCR-ABL1 clone, while another neutrophilic clone containing CSF3R mutations, but not BCR-ABL1, expanded
CSF3R mutations are a hallmark of chronic neutrophilic leukemia (CNL), a rare MPN defined by persistent mature neutrophilic leukocytosis. When the CSF3R variants were detected, the patient’s WBC was 22,800/mm3 with 83% neutrophils, within the range of WHO-defined CNL (11,000–126,000/mm3, median 39,000/mm3). The patient was started on ruxolitinib (5 mg twice daily), which demonstrated efficacy against CNL and CSF3R-mutant atypical CML in a recent clinical trial [12, 13]. With ruxolitinib, the patient’s WBC count decreased slightly and stabilized between 12,800-17,400/mm3, absolute neutrophils between 9700 and 14,300/mm3, platelets were stable at 124,000-155,000/mm3, hemoglobin at 15.3–16.6 g/dL, hematocrit at 46.6–51%. Ruxolitinib was increased to 7.5 mg twice daily after 7 months, which lowered his WBC (8900-13,000/mm3) and absolute neutrophil (6300-10,000/mm3) counts further. At 5.8 years post CML diagnosis and 3.5 years on ponatinib, a third FISH analysis was performed and the (9;22) translocation was still not detectable (200 nuclei).
Discussion and conclusions
This patient had difficulty tolerating tyrosine kinase inhibitors (TKIs), primarily due to hematologic toxicity. While thrombocytopenia is a known side effect of TKIs, the severity and protracted nature of the side effect in this instance suggests dysfunction in the residual BCR-ABL1 negative stem cells. In this case, the emergence of six predicted-pathogenetic variants over the five-year course of treatment suggests that the patient either had a markedly elevated mutational load prior to diagnosis—with different clones emerging in response to TKI selection—or a propensity to develop mutations beyond what is normally associated with aging.
The mutations in BCR-ABL1 and TET2 were present at similar variant allele frequencies at 69 weeks and lost during treatment with dasatinib and ponatinib, suggesting they were present in the same clone. Meanwhile, the CSF3R-mutant clone expanded during BCR-ABL1-directed therapy and is likely independent. Given that the increase in neutrophils began when the patient was switched from dasatinib to ponatinib, it is plausible that the expansion of this clone occurred during treatment with ponatinib specifically. It is known that CSF3R truncating mutations are sensitive to dasatinib [14], and that may have contributed to a delayed onset of this second MPN.
It is well established that selective pressure from TKIs allows for the outgrowth of BCR-ABL1 clones harboring point mutations in ABL1. However, this study suggests that the clearance of a BCR-ABL1 positive clone allowed for the outgrowth of a second, genetically distinct leukemia. It is interesting to note that two granulocytic leukemias arose in this patient, suggesting that either cell intrinsic or microenvironmental factors caused a specific predilection for malignancies of the granulocytic lineage. Germline mutations have not been accessed for this patient. This case describes the exceedingly rare co-occurrence of CML and CNL in the same individual and is an unusual example of clonal evolution under selective pressure from targeted therapy. These findings highlight that myeloid disease with complex clonal architecture is prone to molecular evolution. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Abbreviations
MPNsMyeloproliferative neoplasms
CMLChronic myeloid leukemia
CNLChronic neutrophilic leukemia
PhPhiladelphia
FISHChromosome, Fluorescent In Situ Hybridization
ISInternational scale
TKIsTyrosine kinase inhibitors
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Authors thank colleagues at Arizona Center for Cancer Care and Grande Ronde Hospital for collaboration on the care of the patient.
Authors’ contributions
DB and BJD treated the patient; SAC, TPB and JEM analyzed and/or interpreted the data; SAC and TPB wrote the paper. All authors reviewed and approved the manuscript.
Funding
SAC is supported by a fellowship from the National Cancer Institute, F32CA239422. JEM is supported by an American Society of Hematology Scholar Award, a Gilead Research Scholars Award, and American Cancer Society RSG-19-184-01-LIB. TPB is supported by KL2 TR002370–03 and K08 CA245224–01. BJD is supported by Howard Hughes Medical Institute and R01 CA065823–24.
Availability of data and materials
Data sharing requests should be sent to the corresponding author.
Ethics approval and consent to participate
The OHSU IRB determined that the proposed activity is not research involving human subjects. Access and use of protected health information complies with OHSU HIPAA policies for non-research activities.
Consent for publication
Not applicable. Data presented in this study has been de-identified and contains none of the 18 HIPPA individual identifiers.
Competing interests
B.J.D. potential competing interests–SAB: Aileron Therapeutics, ALLCRON, Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Baxalta (inactive), Monojul (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, Third Coast Therapeutics, GRAIL (inactive), CTI BioPharma (inactive); scientific founder: MolecularMD (inactive, acquired by ICON); board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; founder: VP Therapeutics; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana- Farber Cancer Institute (one Merck exclusive license). B.J.D. potential competing interests– consultant: Monojul, Patient True Talk; SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI Bio-Pharma (inactive); scientific founder and stock: MolecularMD; board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties: OHSU #606-Novartis exclusive license, OHSU #2573; Dana-Farber Cancer Institute #2063- Merck exclusive license. J.E.M. receives grant funding from the Gilead Research Scholars Program. The remaining authors declare no competing interests. | Recovering | ReactionOutcome | CC BY | 33516272 | 19,132,277 | 2021-01-30 |
What was the outcome of reaction 'Thrombocytopenia'? | Outgrowth of a CSF3R-mutant clone drives a second myeloproliferative neoplasm in a chronic myeloid leukemia patient: a case report.
BACKGROUND
Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two myeloproliferative neoplasms with mutually exclusive diagnostic criteria. A hallmark of CML is the Philadelphia chromosome (Ph), which results in a BCR-ABL1 fusion gene and constitutive tyrosine kinase activity. CNL is a Ph-negative neoplasm and is defined in part by the presence of CSF3R mutations, which drive constative JAK/STAT signaling.
METHODS
Here, we report the exceedingly rare co-occurrence of two granulocytic myeloproliferative neoplasms in a 69-year old male patient. After an initial diagnosis of chronic myeloid leukemia, the patient's clinical course was shaped by hematologic toxicity, the emergence of treatment-resistant BCR-ABL1 clones, and the expansion of a CSF3R-mutant clone without ABL1 mutations under selective pressure from tyrosine kinase inhibitors. The emergence of the CSF3R-mutant, neutrophilic clone led to the diagnosis of CNL as a second myeloproliferative neoplasm in the same patient.
CONCLUSIONS
This is the first reported case of CNL arising subsequent to CML, which occurred under selective pressure from targeted therapy in a patient with complex clonal architecture. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Background
Myeloproliferative neoplasms (MPNs) are clonal hematologic malignancies in which a hematopoietic stem cell defect drives proliferation of mature myeloid cell lineages. Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two MPNs with mutually exclusive diagnostic criteria. A hallmark of CML is the presence of the Philadelphia (Ph) chromosome, which results from t (9;22) and separates CML from Ph-negative MPNs: essential thrombocythemia, primary myelofibrosis, polycythemia vera, chronic neutrophilic leukemia [1]. The BCR-ABL1 fusion gene results from t (9;22) and drives the proliferation of mature myeloid cells through constitutive tyrosine kinase activity [2, 3]. In this report, we describe a second rare MPN, chronic neutrophilic leukemia (CNL), arising after a CML patient achieved a complete molecular remission. This is the first reported case of CNL arising subsequent to CML.
Case presentation
A 69-year-old presented initially to his primary care provider with a progressive cough accompanied by weakness, fatigue, and abdominal distension. His white cell count was 113,900/mm3, hemoglobin was 11.8 g/dL, and platelet count was 325,000/mm3. A bone marrow biopsy showed a markedly hypercellular marrow (100%) with ~ 4% blasts, consistent with chronic phase CML. A 300 cell differential showed left-shifted myelopoiesis in which mid-range differentiated granulocytes—myelocytes, metamyelocytes with lesser amounts of promyelocytes—predominated over more differentiated forms. Myeloid and erythroid precursors were present in a 20:1 ratio. Auer rods were not observed. A Fluorescent In Situ Hybridization (FISH) assay confirmed a BCR-ABL1 translocation and cytogenetics revealed the Ph chromosome resulting from a (9;22) translocation. The major BCR-ABL1 transcript (p210) was 66.45% on the international scale (IS). The patient was started on 300 mg of nilotinib twice daily, which reduced his BCR-ABL1 to 0.403% (IS) in 18 weeks. However, the emergence of six new pathogenic mutations as well as hematologic toxicity of ABL1 inhibitors in this case made the treatment course complex (Tables 1, 2).
Table 1 Treatment strategy. The patient had difficulty tolerating TKIs due to hematologic toxicity (thrombocytopenia). Additionally, identification of three genetic variants triggered three treatment changes: imatinib and nilotinib-resistant BCR-ABL1 E255V, ponatinib-sensitive BCR-ABL1 T315I, ruxolitinib-sensitive CSF3R mutations. Dates initiated and discontinued are the number of weeks post-diagnosis of CML
Inhibitor Molecular Target Initiated Discontinued Reason Discontinued
Nilotinib BCR-ABL1 0w 28w Thrombocytopenia
Imatinib BCR-ABL1 33w 78w BCR-ABL1 p.E255V
Dasatinib BCR-ABL1 79w 118w BCR-ABL1 p.T315I
Ponatinib BCR-ABL1 128w
Ruxolitinib CSF3R 252w
Table 2 Variant allele frequencies and BCR-ABL transcript levels 3 years apart for predicted pathogenic mutations. Outgrowth of a CSF3R-mutant clone during treatment with BCR-ABL1 tyrosine kinase inhibitors drives disease evolution from CML to CNL
Gene Variant COSMIC v92
FATHMM prediction Variant Allele Frequency
69 weeks 116 weeks 225 weeks
KMT2C/MLL3 S1860C Pathogenic (score 0.90) 50.62 48.92
CSF3R T618I Pathogenic (score 0.96) 11.58 41.09
CSF3R W818* Pathogenic (score 0.83) 10.22 40.26
TET2 R1167K Pathogenic (score 0.99) 2.86
ABL1 E255V (not annotated) 2.01 Not detected (targeted PCR)
ABL1 T3151 (not annotated) Detected (targeted PCR)
BCR-ABL1 2.50% (IS) 0.508% (IS) 0.000% (IS)
After 18 weeks on nilotinib, the patient presented with chest pain and was found to have pericarditis, atrial fibrillation, and severe thrombocytopenia (platelets at 11,000). The patient was ultimately started on imatinib at 400 mg/day but thrombocytopenia remained problematic. After 2 months, imatinib was reduced to 300 mg/day in an attempt to stabilize the patient’s ongoing thrombocytopenia. His platelets only slightly improved, however BCR-ABL1 transcripts decreased. The 400 mg/day dose was resumed when BCR-ABL1 rose from 0.68 to 2.74% (IS); however, subsequent ABL sequencing detected an imatinib and nilotinib-resistant E255V mutation [4], and the patient switched to dasatinib at 100 mg/day.
The leukemia responded well to dasatinib, though BCR-ABL1 transcript level plateaued above 0.1% (IS), the threshold for a major molecular response. ABL sequencing after 9 months of treatment detected a T315I mutation, which confers resistance to dasatinib, nilotinib, imatinib and bosutinib [5–11]. The patient was switched to ponatinib (30 mg/day) and his BCR-ABL1 transcript levels decreased steadily, falling below 0.1% (IS) after 3 months. The patient tolerated ponatinib well, with no thrombocytopenia. After 2 years on ponatinib, the (9;22) translocation was not detected by FISH in 200 cells scored for BCR (22Q11.2)/ABL (9Q34). Additionally, the BCR-ABL1 fusion gene was no longer detectable by PCR, 0.000% (IS). After 2.5 years, the dose of ponatinib was reduced to 15 mg/day.
Despite the disappearance of the Ph chromosome, the patient’s white blood cell and absolute neutrophil counts rose while on ponatinib, raising concerns about whether a second Ph-negative MPN could be emerging (Fig. 1). A 220 gene next generation sequencing panel was ordered and two CSF3R mutations, T618I and W818*, were identified at a variant allele frequency (VAF) of 41.1 and 40.3%, respectively. Predicted pathogenic variants were identified based on the COSMIC v92 (Catalogue of Somatic Mutations in Cancer) database. Retrospective analysis of an archived marrow sample revealed that the CSF3R mutations had been present for at least the past 3 years. Bone marrow from diagnosis was not available for retrospective next generation sequencing analyses. In total, six predicted-pathogenic variants were detected in the patient over the course of his treatment, including two CSF3R mutations (T618I and W818*), two ABL1 mutations (E255V and T315I), KMT2C/MLL3 (S1860C), and TET2 (R1167K) (Table 2).
Fig. 1 Emergence of a CSF3R-mutant, neutrophilic leukemia during targeted therapy for BCR-ABL1. Hematologic toxicity and the emergence of treatment-resistant clones shaped this CML patient’s clinical course. Ultimately, treatment with ponatinib successfully controlled the BCR-ABL1 clone, while another neutrophilic clone containing CSF3R mutations, but not BCR-ABL1, expanded
CSF3R mutations are a hallmark of chronic neutrophilic leukemia (CNL), a rare MPN defined by persistent mature neutrophilic leukocytosis. When the CSF3R variants were detected, the patient’s WBC was 22,800/mm3 with 83% neutrophils, within the range of WHO-defined CNL (11,000–126,000/mm3, median 39,000/mm3). The patient was started on ruxolitinib (5 mg twice daily), which demonstrated efficacy against CNL and CSF3R-mutant atypical CML in a recent clinical trial [12, 13]. With ruxolitinib, the patient’s WBC count decreased slightly and stabilized between 12,800-17,400/mm3, absolute neutrophils between 9700 and 14,300/mm3, platelets were stable at 124,000-155,000/mm3, hemoglobin at 15.3–16.6 g/dL, hematocrit at 46.6–51%. Ruxolitinib was increased to 7.5 mg twice daily after 7 months, which lowered his WBC (8900-13,000/mm3) and absolute neutrophil (6300-10,000/mm3) counts further. At 5.8 years post CML diagnosis and 3.5 years on ponatinib, a third FISH analysis was performed and the (9;22) translocation was still not detectable (200 nuclei).
Discussion and conclusions
This patient had difficulty tolerating tyrosine kinase inhibitors (TKIs), primarily due to hematologic toxicity. While thrombocytopenia is a known side effect of TKIs, the severity and protracted nature of the side effect in this instance suggests dysfunction in the residual BCR-ABL1 negative stem cells. In this case, the emergence of six predicted-pathogenetic variants over the five-year course of treatment suggests that the patient either had a markedly elevated mutational load prior to diagnosis—with different clones emerging in response to TKI selection—or a propensity to develop mutations beyond what is normally associated with aging.
The mutations in BCR-ABL1 and TET2 were present at similar variant allele frequencies at 69 weeks and lost during treatment with dasatinib and ponatinib, suggesting they were present in the same clone. Meanwhile, the CSF3R-mutant clone expanded during BCR-ABL1-directed therapy and is likely independent. Given that the increase in neutrophils began when the patient was switched from dasatinib to ponatinib, it is plausible that the expansion of this clone occurred during treatment with ponatinib specifically. It is known that CSF3R truncating mutations are sensitive to dasatinib [14], and that may have contributed to a delayed onset of this second MPN.
It is well established that selective pressure from TKIs allows for the outgrowth of BCR-ABL1 clones harboring point mutations in ABL1. However, this study suggests that the clearance of a BCR-ABL1 positive clone allowed for the outgrowth of a second, genetically distinct leukemia. It is interesting to note that two granulocytic leukemias arose in this patient, suggesting that either cell intrinsic or microenvironmental factors caused a specific predilection for malignancies of the granulocytic lineage. Germline mutations have not been accessed for this patient. This case describes the exceedingly rare co-occurrence of CML and CNL in the same individual and is an unusual example of clonal evolution under selective pressure from targeted therapy. These findings highlight that myeloid disease with complex clonal architecture is prone to molecular evolution. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.
Abbreviations
MPNsMyeloproliferative neoplasms
CMLChronic myeloid leukemia
CNLChronic neutrophilic leukemia
PhPhiladelphia
FISHChromosome, Fluorescent In Situ Hybridization
ISInternational scale
TKIsTyrosine kinase inhibitors
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Acknowledgements
Authors thank colleagues at Arizona Center for Cancer Care and Grande Ronde Hospital for collaboration on the care of the patient.
Authors’ contributions
DB and BJD treated the patient; SAC, TPB and JEM analyzed and/or interpreted the data; SAC and TPB wrote the paper. All authors reviewed and approved the manuscript.
Funding
SAC is supported by a fellowship from the National Cancer Institute, F32CA239422. JEM is supported by an American Society of Hematology Scholar Award, a Gilead Research Scholars Award, and American Cancer Society RSG-19-184-01-LIB. TPB is supported by KL2 TR002370–03 and K08 CA245224–01. BJD is supported by Howard Hughes Medical Institute and R01 CA065823–24.
Availability of data and materials
Data sharing requests should be sent to the corresponding author.
Ethics approval and consent to participate
The OHSU IRB determined that the proposed activity is not research involving human subjects. Access and use of protected health information complies with OHSU HIPAA policies for non-research activities.
Consent for publication
Not applicable. Data presented in this study has been de-identified and contains none of the 18 HIPPA individual identifiers.
Competing interests
B.J.D. potential competing interests–SAB: Aileron Therapeutics, ALLCRON, Cepheid, Vivid Biosciences, Celgene, RUNX1 Research Program, EnLiven Therapeutics, Gilead Sciences (inactive), Baxalta (inactive), Monojul (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, Third Coast Therapeutics, GRAIL (inactive), CTI BioPharma (inactive); scientific founder: MolecularMD (inactive, acquired by ICON); board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; founder: VP Therapeutics; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties from Patent 6958335 (Novartis exclusive license) and OHSU and Dana- Farber Cancer Institute (one Merck exclusive license). B.J.D. potential competing interests– consultant: Monojul, Patient True Talk; SAB: Aileron Therapeutics, ALLCRON, Cepheid, Gilead Sciences, Vivid Biosciences, Celgene & Baxalta (inactive); SAB and stock: Aptose Biosciences, Blueprint Medicines, Beta Cat, GRAIL, Third Coast Therapeutics, CTI Bio-Pharma (inactive); scientific founder and stock: MolecularMD; board of directors and stock: Amgen; board of directors: Burroughs Wellcome Fund, CureOne; joint steering committee: Beat AML LLS; clinical trial funding: Novartis, Bristol-Myers Squibb, Pfizer; royalties: OHSU #606-Novartis exclusive license, OHSU #2573; Dana-Farber Cancer Institute #2063- Merck exclusive license. J.E.M. receives grant funding from the Gilead Research Scholars Program. The remaining authors declare no competing interests. | Recovering | ReactionOutcome | CC BY | 33516272 | 19,132,277 | 2021-01-30 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal impairment'. | Renal medication-related clinical decision support (CDS) alerts and overrides in the inpatient setting following implementation of a commercial electronic health record: implications for designing more effective alerts.
To assess the appropriateness of medication-related clinical decision support (CDS) alerts associated with renal insufficiency and the potential/actual harm from overriding the alerts.
Override rate frequency was recorded for all inpatients who had a renal CDS alert trigger between 05/2017 and 04/2018. Two random samples of 300 for each of 2 types of medication-related CDS alerts associated with renal insufficiency-"dose change" and "avoid medication"-were evaluated by 2 independent reviewers using predetermined criteria for appropriateness of alert trigger, appropriateness of override, and patient harm.
We identified 37 100 "dose change" and 5095 "avoid medication" alerts in the population evaluated, and 100% of each were overridden. Dose change triggers were classified as 12.5% appropriate and overrides of these alerts classified as 90.5% appropriate. Avoid medication triggers were classified as 29.6% appropriate and overrides 76.5% appropriate. We identified 5 adverse drug events, and, of these, 4 of the 5 were due to inappropriately overridden alerts.
Alerts were nearly always presented inappropriately and were all overridden during the 1-year period studied. Alert fatigue resulting from receiving too many poor-quality alerts may result in failure to recognize errors that could lead to patient harm. Although medication-related CDS alerts associated with renal insufficiency had previously been found to be the most clinically beneficial alerts in a legacy system, in this system they were ineffective. These findings underscore the need for improvements in alert design, implementation, and monitoring of alert performance to make alerts more patient-specific and clinically appropriate.
pmcINTRODUCTION
Adverse drug events (ADEs), defined as medication-related injuries, occur in approximately 1.5 million inpatients every year in the United States (US).1 Some studies suggest ADEs account for 5%–17% of hospital admissions.2–5 Of the 1.5 million ADEs occurring in the US annually, approximately 400 000 are considered preventable. Patients with renal insufficiency are at high risk for ADEs due to drug accumulation secondary to reduced renal elimination. They are also at higher risk of medication induced kidney damage than patients without preexisting kidney injury. Polypharmacy and comorbidities also increase the risk of ADEs for this vulnerable population.6–10 Given their association with increase in hospital length of stay, costs, and morbidity and mortality, efforts have been made to reduce the frequency of ADEs.11–14
One method for preventing ADEs is implementing medication-related clinical decision support (CDS); this can be especially effective in patients with renal insufficiency.15 Overall, medication-related CDS systems have been shown to reduce medication errors by 81%, although these data came from legacy, homegrown applications.8,16 Even though electronic health records (EHRs) at most hospitals include some form of CDS, most of this CDS currently is vendor-developed, and often does not address medication use in patients with renal insufficiency. It has been reported that one-third of patients receive inappropriate doses based on renal function.10
Medication-related CDS represents an effective way to reduce errors, and ADEs.17–19 However, this impact may be decreased or even extinguished if too many clinically inappropriate alerts are given.20–22 This problem represents an important one in informatics today, as EHRs are now broadly implemented, and almost all are vendor-developed. One study reported approximately 60% of overrides of alerts were appropriate and the override rates varied based on type.23 Duplication medication alerts were appropriately overridden 98.0% of the time, drug allergy alerts were appropriately overridden 96.5% the time, non-formulary medication alerts were appropriately overridden 82.5% of the time, drug–drug interaction alerts were appropriately overridden 26.4% of the time, age-based medication substitution alerts were appropriately overridden 26.4% of the time and medication-related CDS alerts associated with renal insufficiency were appropriately overridden 2.2% of the time. Many other studies have found higher override rates.23,24 Alert fatigue introduces the risk of missing critical alerts that may compromise patient safety.25–28 A study performed at our institution using a legacy, homegrown EHR system found that inappropriately overridden CDS alerts were associated with an increased risk of ADEs.29
Few studies have evaluated the quality of CDS alerts in commercial systems by measuring frequency and appropriateness of alert overrides or ADEs resulting from overrides of alerts. The objective of this study was to analyze the appropriateness of medication-related CDS alerts associated with renal insufficiency, assess appropriateness of alert overrides, and assess the potential harm from overriding alerts.
MATERIALS AND METHODS
Study population
This study was performed at Brigham and Women’s Hospital, Boston, MA, a large urban academic medical center that uses a leading vendor EHR system in the US. We performed a retrospective evaluation of medication-related CDS alerts associated with renal insufficiency in adult inpatients (including the ICU and step-down units) from 05/2017 to 04/2018. All patients ≥ 18 years who had a medication-related CDS alert associated with renal insufficiency were included. Data for total number of alerts and alert override frequency was collected. There were 2 types of medication-related CDS alerts associated with renal insufficiency at our medical center. The first type, intended to convey a recommendation to adjust the medication dose, stated: “Specific dosing guidelines are not available for this patient’s level of renal impairment.” This alert fired for specific renally cleared medications such as gabapentin and potassium chloride when a patient did not have a recent serum creatinine value. The second type of alert stated: “This drug is not recommended for this patient’s level of renal impairment (CrCl 0–30).” This alert fired for some medications such as Nitrofurantoin and potassium chloride but only if the patient had a recent serum creatinine indicating renal function was below normal range but not necessarily impaired to a level at which the drug should be avoided. The alerts only consider serum creatinine levels drawn during the patient’s current hospital admission. For the second type of medication-related CDS alert associated with renal insufficiency, CrCl ranges were provided based on dosing guidelines for the specific medication recommended by our medication knowledge base, a third-party provider (First Databank, South San Francisco, CA). For example, if a physician prescribed nitrofurantoin, the alert stated, “This drug is not recommended for this patient’s level of renal impairment (CrCl 0–60).” However, this range of CrCl did not always correlate with the patient’s actual renal impairment. For example, a patient with a slightly lower than normal CrCl of 80mL/min would still receive an alert stating “This drug is not recommended for this patient’s level of renal impairment (CrCl 0–60)” as the alert fired based on drug prescribed not the patient’s actual level of renal impairment. An example of a medication for which either type of alert could present is potassium chloride. Orders for this medication in patients without a recent serum creatinine level would get a “dosing guidelines not available” alert and for patients with a recent serum creatinine indicating reduced renal function would get a “this drug not recommended” warning. In addition, the same patient could potentially receive the first type of warning initially and the second type of warning after a serum creatinine was obtained. The only time a medication-related CDS alert associated with renal insufficiency would remain silent is when the patient had a normal CrCl. For example, if a physician ordered potassium chloride and the patient had an estimated CrCl of 100ml/min, there would be no alert. The data on each alert trigger was obtained from our institution’s enterprise data warehouse. All data were collected with approval from Brigham and Women’s Hospital Institutional Review Board.
Chart reviews alert and overrides and ADEs
Random samples of 300 cases of the first type of alert “specific dosing guidelines are not available for this patient’s level of renal impairment” and 300 cases of the second type of alert “this drug is not recommended for this patient’s level of renal impairment,” stratified by level of renal impairment range provided in the alert, were reviewed for appropriateness. The renal alert strata were CrCl < 30, CrCl 31–60, and CrCl > 60. Data collected included the alert, the triggering medication, and the patient’s creatinine clearance if overridden.
The alerts were independently reviewed by 2 clinical pharmacists (1 with significant experience with renal transplant patients and 1 with significant experience in medication safety) based on 3 criteria: 1) alert appropriateness based on the triggering medication, 2) appropriateness of the override, and if the medication was administered; 3) occurrence of an ADE. Final criteria for alert trigger appropriateness and alert override appropriateness were discussed between the 2 reviewers and modified until a consensus was reached and are included in Figure 1 and Figure 2. Criteria considered for determining appropriateness included: comfort measure only (ie, hospice), chronic vs acute renal insufficiency, strong medication contraindication, 1-time dose, laboratory monitoring, and dialysis. Information on these characteristics was either extracted from the enterprise data warehouse or obtained by manual review of patient EHRs. Chronic renal insufficiency was defined as abnormalities of kidney structure or function, present for over 3 months with implications for health, based on cause, glomerular filtration rate (GFR) category and albuminuria category based on KDIGO guidelines. Acute renal insufficiency was defined as increase in SCr by ≥ 0.3 mg/dl within 48 hours or increase in SCr ≥ 1.5 times baseline which is known to have occurred within the prior 7 days or urine volume < 0.5ml/kg/h for 6 hours. Criteria for appropriateness of override were adapted based on previously published data, including guidelines as well as clinical experience (Figure 2).23,30 Overridden alerts for medications that were not administered were included in the analysis of whether the alert trigger was appropriate and whether the alert override was appropriate but were excluded for the evaluation of ADEs as the medication never reached the patient. Inappropriate overrides for medications that did not reach the patient were considered potential ADEs. If different medications triggered unique alerts in the same patient, both alerts were reviewed and included in the dataset. However, only 1 alert per medication was allowed. Thus, multiple alerts triggered by the same medication for the same patient were excluded. Alerts for medications given for diagnostic procedures, and anesthesia in the OR, were also excluded, as there is typically no alternative and are 1-time doses. Baseline patient characteristics were collected for demographics.
Figure 1. Criteria for appropriateness of alert trigger.
Figure 2. Criteria for appropriateness of alert override.
To evaluate for ADEs, charts were reviewed for all patients in the random sample in which the medication was administered regardless of override appropriateness. The inter-rater agreement for appropriateness of alert triggers, appropriateness of override, and presence of ADE was determined with a Cohen’s k statistic. Disagreements were resolved by discussion between the 2 reviewers. If consensus could not be achieved, a third reviewer (a physician with significant experience in medication and patient safety, and in some cases, a nephrologist) was consulted.
ADE evaluation
An ADE was defined as an injury occurring from use of the triggering medication. We included instances where the patient’s serum creatinine increased between 10% and100% from baseline, which was considered a significant ADE. Baseline serum creatinine was the most recent inpatient serum creatinine prior to alert firing. An increase in serum creatinine could indicate further renal decline, and could be a result of overriding a drug or dose that was inappropriate given the patient’s baseline renal function. If serum creatinine increased more than 2-fold compared to baseline, this was classified as a serious ADE. Another type of ADE included electrolyte disturbances such as hyperkalemia, hyponatremia, hypermagnesemia, hypercalcemia and metabolic acidosis. These were defined by the reference ranges of the lab utilized at our institution. Hyperkalemia was defined as potassium levels above 5.5 mEq/L, with a level of above 6.0 considered moderate and anything above 7.0 mEq/L considered severe. Hyponatremia was defined as sodium levels below 135 mEq/L, with a level of 120–130 considered moderate hyponatremia and anything under 120 severe. Hypermagnesemia was defined as magnesium level above 2.2 mg/dL, with a level above 3 as moderate and anything above 7 mg/dL was considered severe. Hypercalcemia was defined as calcium level above 10mg/dL, with a level of 11.5 as moderate and anything above 12 severe. Metabolic acidosis was defined as a bicarbonate level below 15mEq/L and an anion gap greater than 12. The period of evaluation for ADE started after the alert override and continued for the remainder of the patient’s admission. Only ADEs that were specific to the overridden alert were included in analysis. Data relevant to override appropriateness and ADEs such as laboratory reports, medication orders, and patient notes documented by nurse or providers were abstracted and summarized by the reviewers. This was done so the ADES could be classified as either preventable or nonpreventable. ADEs were classified as preventable if there was an error associated with the ADE (which aligned with the appropriateness of an override). Study personnel had undergone training based on guidance developed by the Center for Excellence for Patient Safety Research at Brigham and Women’s Hospital, which has been described and used in previous studies.27 The rates of inappropriate alert triggers, appropriate alert triggers, inappropriate overrides, appropriate overrides, and number of ADEs were calculated.
RESULTS
Our total study population consisted of 10 263 patients who received a medication-related CDS alert associated with renal insufficiency during the study period (Table 1). The 600 randomly selected alerts we reviewed occurred in 532 unique patients.
Table 1. Patient demographics
Gender Number (%)
Female 5464 (53.2)
Male 4779 (46.8)
Race Number
White 8089 (78.8)
Black/African 1099 (10.7)
Other 360 (3.5)
Hispanic/Latino 233 (2.2)
Asian 235(2.3)
Unknown 247(2.4)
Mean Age
70 (19–104)
Location of Alerts Number
Non-ICU Alerts 35 940 (85.2)
ICU Alerts 6255 (14.8)
Frequency of medication-related CDS alerts associated with renal insufficiency
There were 37 100 “specific dosing” guideline alerts, and 100% of these were overridden (Table 2). There were 5095 “this drug is not recommended” alerts and 100% were also overridden (Table 2).
Table 2. Renal alert overrides
“Specific dosing guidelines are not available for this patient’s level of renal impairment” Alerts (%) “This drug is not recommended for this patient’s level of renal impairment” Alerts (%)
Number of Alerts 37 100 5095
Appropriate Alert Triggersa 12.5% 29.6%
Inappropriate Alert Triggersa 87.5% 70.4%
Number of Overridden Alerts 37 100 (100) 5095 (100)
Appropriate Overridesa 90.5% 76.5%
Inappropriate Overridesa 9.5% 23.5%
a From a sample of 300 charts reviewed for dose alerts and 300 charts reviewed for drug not recommended alerts.
Specific dosing guideline alerts (“specific dosing guidelines are not available for this patient’s level of renal impairment”)
The random sample of 300 alerts reviewed represented 0.81% of the total number of alerts triggered. Of these alerts, 5 (1.7%) alerts associated with medications given for diagnostic procedures were excluded. The remaining 295 alerts were included in the analysis. The top 5 drugs that triggered alerts (Table 3) were gabapentin, vancomycin, potassium chloride, furosemide, and calcium gluconate. The Cohen’s k statistic for appropriateness of alert trigger was 0.96 (CI: 0.91–1.0), and for appropriateness of alert override was 0.92 (CI: 0.84–1.0), both showing a high level of agreement between the 2 reviewers. Alert triggers were classified as appropriate in 12.5% of cases (n = 38), and inappropriate in 87.5% of cases (n = 257) (Table 2). Alerts were determined to be overridden appropriately 90.5% of the time (n = 267) and inappropriately 9.5% of the time (n = 28). Overall, 81.7% (n = 241) of the medications reached the patient.
Table 3. Top 5 medications triggering specific dosing guideline alerts
Total sample drug name Total number of alerts N = 37 100 (%)
Gabapentin 5080 (13.7)
Vancomycin 3105 (8.4)
Potassium Chloride 3809 (10.3)
Furosemide 2146 (5.8)
Calcium Gluconate 2050 (5.5)
This drug not recommended alerts (“this drug is not recommended for this patient’s level of renal impairment”)
The random sample of 300 alerts reviewed represented 5.9% of the total alerts triggered. Of these, 23 (7.7%) alerts associated with medications given for diagnostic procedures were excluded, leaving 277 alerts in the analysis. The top 5 drugs that triggered alerts were potassium chloride, cholecalciferol, chlorothiazide sodium, magnesium oxide, and desmopressin (Table 4). The Cohen’s k statistic for appropriateness of alert trigger was 0.96 (CI: 0.92 –0.99) and for appropriateness of override was 0.96 (CI: 0.92–1.0). Alert triggers were classified as appropriate in 29.6% of cases (n = 82) and inappropriate in 70.4% of cases (n = 195) Table 2) Alert overrides were determined to be appropriate 76.5% of the time (n = 212) and inappropriate 23.5% of the time (n = 65). Overall, 68.2% (n = 189) of the medications reached the patient.
Table 4. Top 5 medications that triggered “This drug is not recommended for this patient’s level of renal impairment alert”
Total sample drug name Number of alerts N = 5095 (%)
Potassium Chloride 1894 (37.2)
Cholecalciferol 478 (9.4)
Chlorothiazide Sodium 377 (7.4)
Magnesium oxide 328 (6.4)
Desmopressin 274 (5.4)
Adverse drug events
The Cohen’s k statistic for presence of ADEs was 0.99 (CI: 0.94–1.0). Only 5 ADEs were identified; all were significant. Of these, 4 of the 5 ADEs were considered preventable, and 1 was judged nonpreventable. In 1 case, fenofibrate was administered to the patient at a dose that was too high based on their renal function. This resulted in a significant increase in creatinine kinase (CK) and worsening renal function and the drug had to be stopped. In another case, a patient’s furosemide dosage was increased from 20 mg to 160mg abruptly, leading to worsening kidney function. In a third case, the patient received a single dose of magnesium, when the patient’s magnesium levels were already within normal range, resulting in a markedly elevated magnesium level of 5.5 and stopping of the medication. In addition, a patient with acute kidney injury received chlorothiazide which resulted in worsening kidney function. In the case judged nonpreventable, the patient received calcium acetate for high phosphate levels, resulting in elevated calcium levels even though the phosphate levels remained elevated.
DISCUSSION
We evaluated medication-related CDS alerts associated with renal insufficiency delivered in our vendor EHR and found that all these alerts were overridden, in contrast to the performance of alerts in the past which had been quite effective and had been demonstrated to improve dosing accuracy and decrease length of stay.15 In this study, nearly 9 out of 10 alerts were classified as inappropriate, and therefore the majority of alert overrides were considered appropriate.
The override rate was much higher than previous studies, but the appropriateness of alert overrides was consistent with previous studies.30,31 These data demonstrate that there is substantial room for improvement in our current process in several areas, including the monitoring approach, accuracy of alerts, and how suggestions are delivered. We have shared these data with the operational team who has made improvements in alerts for selected medications including vancomycin and furosemide, 2 frequently used medications with high risk of harm if dosed inappropriately. The improvements include decreasing the CrCl threshold at which an alert would fire to reduce the number of alerts shown to providers.
We found 5 ADEs in the cases we reviewed, 4 of which were preventable. Clearly, this issue needs to be addressed to reduce the frequency of medication-related harm. This is very unlikely to be a local issue, as the vendors evaluated both for EHR and medication knowledge base are 2 of the most widely implemented in the US.
There are several potential reasons why our current medication-related CDS alerts associated with renal insufficiency are less effective than they had been in the legacy homegrown system:
No automatic calculation of level of renal function (CrCl or estimated GFR)
No automatic dose adjustment
No recommendations for alternatives
No consideration of patient specific parameters, such as dialysis
In the past, the EHR calculated the patient’s estimated GFR and, if a nephrotoxic or renally excreted medication was ordered, had the application default to the appropriate dose and frequency given that patient’s kidney function, so that it was easy for providers to select the correct dose for the individual patient. However, our current vendor EHR does not allow tailoring of dosage based on a patient’s level of renal function. Furthermore, in the current application, multiple alerts fire at once with most being low-value, and the new system gives the provider the ability to override all alerts at once. This ability to override all alerts at once allows physicians to skip reviewing many alerts which we did not previously allow, although we were much more selective about delivering them.
By analyzing the renal insufficiency triggers, we showed that most alert triggers were in fact inappropriate. Alerts fired even when the patient did not have renal insufficiency or if the dose had already been adjusted for renal function. The alerts do not consider inpatient lab values for renal function that are drawn on the same day as the alert. Some common examples of alerts that were considered inappropriate were those for low dose aspirin, potassium chloride, and vancomycin. Other examples include alerts for single doses of electrolytes or diuretics when the patient is being monitored and alerts firing when dose had been adjusted appropriately for renal function of the patient. Even when the patient did have renal insufficiency, the alerts did not provide insightful or helpful information to providers, which is consistent with previous studies that have identified that better design and implementation are needed for renal medication CDS.32 One alert simply stated that, “This drug is not recommended for this patient’s level of renal impairment,” which was triggered for a drug that would require dosing adjustment based on a recent serum creatinine available for the patient. The second alert stated “Specific dosing guidelines are not available for this drug based on patient renal impairment,” which was triggered for a drug that required renal dose adjustment when no recent serum creatinine was available. Neither of these alerts provided physicians with any further guidance. These characteristics violate basic human factors principles around alerting.32 Since nearly all these alerts were inappropriate, it is not surprising that clinicians developed alert fatigue. Physicians become desensitized to important renal insufficiency alert triggers, as most alert triggers become white noise. This also leads to inappropriate alert overrides which could lead to patient harm. Inappropriate alert overrides have the potential of causing harm, although in this study we only identified a few ADEs that occurred in the inappropriate alert overrides that were administered to the patient. Overrides that presented significant risk may have been more often intercepted before reaching the patient. In addition, inadequate documentation of some types of ADEs in the chart may have prevented identification of some ADEs that occurred during the hospital admission, resulting in underestimation of ADE incidence.
One way to improve renal CDS alert triggers is to create alert triggers that offer recommendations for alternative medications to physicians. A previous study conducted at BWH using the hospital’s in-house developed legacy, homegrown EHR system showed that when physicians were provided with alternatives, high warning alert triggers were accepted 100% of the time.33–35 Lastly, the alert triggers do not currently consider patient-specific parameters, such as dialysis or end of life care. Alert triggers should take these factors into consideration before firing to reduce alert burden presented to providers.
This study has several limitations. We retrospectively evaluated the alerts; therefore, it is hard to tell why a physician may have overridden the alert and challenging to identify all patient harm. Identification of ADEs requires adequate documentation in the EHR, which does not always occur. We also only evaluated ADEs that were documented during hospitalization and did not follow up on patients after discharge, where they could have remained on the drug and developed ADEs that take longer to manifest. This study was done at 1 site, so these results might not be generalizable. Our institution utilizes an EHR and knowledge base that may not be used at other institutions. Alert logic from knowledge bases are based on set criteria but may be tailored to institution-specific needs. However, given that the EHR we use is among the most commonly adopted, we believe that our situation applies to a significant number of other institutions with a similar commercial EHR.31
CONCLUSION
We evaluated renal CDS alert triggers in a newly implemented commercial EHR and found that all were overridden. Most alerts were appropriately overridden, though this was the case because the alert frequency was so high—this problem of over-alerting is a critical issue in informatics today and highlights the need to redesign medication-related CDS alerts associated with renal insufficiency. Even with a high rate of appropriately overridden alerts we discovered 4 ADEs out of 5 that could have been prevented if the alerts fired more appropriately. Future studies should focus on application of human factors principles in redesigning and implementing medication-related CDS alerts associated with renal insufficiency, with a goal of reducing the number of inappropriate alerts presented to providers by making alerts more patient-specific and clinically appropriate. Specifically, these alerts should automatically calculate GFR, suggest an adjusted dose or frequency for that patient, recommend alternatives when appropriate, and consider other patient-specific parameters, such as whether or not the patient is on dialysis.
FUNDING
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
AUTHOR CONTRIBUTIONS
SNS and DLS made substantial contributions to the conception of the design the work and interpretation of data; DWB supervised the research design and contributed to the writing and revision of the manuscript. KGA, MGA, and SNS assisted in the data collection and interpretation. All authors give approval for the final version to be published and agree to be accountable for all aspects of the work, ensuring that any questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
CONFLICT OF INTEREST STATEMENT
Dr. Bates consults for EarlySense, which makes patient safety monitoring systems. He receives cash compensation from CDI (Negev), Ltd, which is a not-for-profit incubator for health IT startups. He receives equity from ValeraHealth which makes software to help patients with chronic diseases. He receives equity from Clew which makes software to support clinical decision-making in intensive care. He receives equity from MDClone which takes clinical data and produces deidentified versions of it. He receives equity from AESOP which makes software to reduce medication error rates. He receives research funding from IBM Watson Health. He serves as a Visiting Professor at Stavanger University. The other authors have no conflicts of interest to declare. | FUROSEMIDE | DrugsGivenReaction | CC BY-NC | 33517413 | 19,969,718 | 2021-06-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ankylosing spondylitis'. | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
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Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | BETAMETHASONE DIPROPIONATE, CLINDAMYCIN PHOSPHATE, CYCLOSPORINE, LIDOCAINE HYDROCHLORIDE, MYCOPHENOLATE MOFETIL, PREDNISONE, SULFASALAZINE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33517879 | 18,915,565 | 2021-01-31 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arthralgia'. | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
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Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chronic kidney disease'. | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | BETAMETHASONE DIPROPIONATE, CLINDAMYCIN PHOSPHATE, CYCLOSPORINE, LIDOCAINE HYDROCHLORIDE, MYCOPHENOLATE MOFETIL, PREDNISONE, SULFASALAZINE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33517879 | 18,915,565 | 2021-01-31 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Joint effusion'. | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Joint warmth'. | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
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Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oedema peripheral'. | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
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Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pain'. | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | BETAMETHASONE DIPROPIONATE, CLINDAMYCIN PHOSPHATE, CYCLOSPORINE, LIDOCAINE HYDROCHLORIDE, MYCOPHENOLATE MOFETIL, PREDNISONE, SULFASALAZINE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33517879 | 18,915,565 | 2021-01-31 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Proteinuria'. | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
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Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | BETAMETHASONE DIPROPIONATE, CLINDAMYCIN PHOSPHATE, CYCLOSPORINE, LIDOCAINE HYDROCHLORIDE, MYCOPHENOLATE MOFETIL, PREDNISONE, SULFASALAZINE, VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33517879 | 18,915,565 | 2021-01-31 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Septic arthritis streptococcal'. | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33517879 | 19,794,934 | 2021-01-31 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Streptococcal infection'. | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
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Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33517879 | 19,794,934 | 2021-01-31 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tenderness'. | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
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Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISONE | DrugsGivenReaction | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
What was the administration route of drug 'BETAMETHASONE DIPROPIONATE'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | Intrathecal | DrugAdministrationRoute | CC BY | 33517879 | 18,915,565 | 2021-01-31 |
What was the administration route of drug 'LIDOCAINE HYDROCHLORIDE'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | Intrathecal | DrugAdministrationRoute | CC BY | 33517879 | 18,915,565 | 2021-01-31 |
What was the administration route of drug 'SULFASALAZINE'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
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Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | Oral | DrugAdministrationRoute | CC BY | 33517879 | 18,915,565 | 2021-01-31 |
What was the dosage of drug 'SULFASALAZINE'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | 500 mg (milligrams). | DrugDosage | CC BY | 33517879 | 18,915,565 | 2021-01-31 |
What was the outcome of reaction 'Ankylosing spondylitis'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | Recovered | ReactionOutcome | CC BY | 33517879 | 18,915,565 | 2021-01-31 |
What was the outcome of reaction 'Arthralgia'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
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Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | Recovered | ReactionOutcome | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
What was the outcome of reaction 'Joint effusion'? | Post-transplant manifestation of ankylosing spondylitis: a case report and review of literature.
Ankylosing spondylitis (AS) is an insidiously progressive and debilitating form of arthritis involving the axial skeleton, characterized by chronic back pain and progressive spinal stiffness, and lessening of pain and stiffness with exercise. Due to subsequent manifestation in different organs, AS causes reduction in life expectancy, so early diagnosis and treatment are of great importance. No AS cases have been reported in solid-organ transplant recipients yet.
A 58-year-old woman with end-stage renal disease due to chronic glomerulonephritis, after allogenic kidney transplantation 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A, mycophenolate mofetil, and prednisone, with no previous history of a connective tissue disease presented fever up to 39 °C accompanied by pain localized in sacroiliac region radiating to the left lower limb. Detailed diagnostic procedures and x-rays of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of AS. Sulphasalazine was added to standard immunosuppression regimen with good clinical results.
We report an adult kidney transplant recipient with a new onset of AS. The risk of relapse or new onset of inflammatory disease in transplant recipients is extremely low due to immunosuppressive therapy following transplantation. However, when it occurs, the clinical presentation is commonly atypical, often leading to delayed diagnosis.
Background
The appearance of inflammatory and autoimmune diseases is quite low in patients after solid organ transplantation [1]. Adequate immunosuppressive therapy usually mitigates the risk of relapse or new onset of an autoimmune disease in this population [2]. The clinical presentation of inflammatory diseases in patients after transplantation is commonly atypical, often leading to delayed diagnosis.
Musculoskeletal pain is a common problem in kidney transplant (KTx) recipients, however, an acute inflammatory arthritis is rare. The differential diagnosis of joint and back pain is broad and includes septic arthritis, systemic infection, crystal arthropathies, autoimmune rheumatologic disorders, and medication-related adverse reactions [3].
Ankylosing spondylitis (AS), previously known as Bechterew’s disease, is a chronic, progressive inflammatory disease with a diverse clinical presentation [3]. AS is characterized by inflammation and new bone formation leading to fusion of the spine and sacroiliac joints. Chronic back pain, progressive spinal stiffness and improvement of pain and stiffness with exercise are the most common features of the disease [4]. Other musculoskeletal manifestations of AS include arthritis, enthesitis and dactylitis [5]. Clinical symptoms most frequently begin in late adolescence or in young adults, with 80% before the age of 30 and with a 3:1 to 2:1 male to female ratio [6, 7].
In addition to spinal inflammation, AS is characterized by a broad clinical spectrum of the extra-articular manifestations like uveitis, psoriasis, inflammatory bowel disease, or aortic insufficiency [8, 9] as well as an increased cardiovascular risk, several pulmonary, renal, and neurological complications or depression [10].
We present a case of late onset of seronegative spondyloarthropaty in KTX patient despite ongoing immunosuppressive treatment. The following description applies to become unusual both in terms of gender, age, comorbidities of the patient, as well as the fact that the patient was constantly treated with triple immunosuppressive regimen.
Case presentation
A 58-year-old woman with end-stage renal disease caused by chronic glomerulonephritis, after allogenic KTx 25 years earlier, with stable, good graft function, treated with chronic immunosuppressive therapy based on cyclosporine A (CsA), mycophenolate mofetil (MMF), and prednisone, with no previous history of a connective tissue disease was admitted to the Nephrology Department with fever up to 39 °C accompanied by pain localized in the sacroiliac region radiating to the left lower limb of 2 weeks duration. Physical examination revealed nothing specific, her vital signs were stable. Initial laboratory data indicated an elevated C-reactive protein (CRP) concentration to 287 mg/l (normal range < 5 mg/l), white blood count (WBC) was 6.4 × 10 3/μl, haemoglobin concentration 10.6 g/dl, serum procalcitonin was negative. Urinalysis showed proteinuria 0.1 g/l, and 15 to 20 leukocytes /higher-power field (HPF), with no erythrocytes in urinary sediment. The graft function was stable (serum creatinine concentration (sCr) 95 μmol/l with estimated glomerular filtration rate (eGFRCKD-EPI) - 57.2 ml/min/1.73m2), serum uric acid was 7.8 mg/dl (normal range 4.2–6.8 mg/dl), alanine and aspartate aminotransferase as well as bilirubin concentration were within normal limits. The blood level of CsA was in the range appropriate to the period after KTx. Hepatitis B, hepatitis C, HIV and CMV DNA tests were negative. Urine and blood culture were negative. Echocardiography was performed, but revealed nothing specific and endocarditis was excluded. The empiric antibiotic therapy with clindamycin was started. Nuclear magnetic resonance (NMR) of the lumbar spine was firstly described as inconclusive, although the patient complained of constant pain aggravation. On the tenth day of hospitalization oedema with a tenderness of the left knee appeared. Due to exudates and excessive warmth of the left knee, arthrocentesis was performed. Sixty millilitres of turbid fluid was withdrawn. The synovial fluid was positive for Streptococcus sp. (saprophytic flora) thus a prolonged, targeted vancomycin therapy was started (the patient was allergic to penicillin). Gout was excluded. Moreover, because of the resistant pain and oedema of the left lower limb, Doppler ultrasound was performed and showed active deep vein thrombosis. Low molecular weight heparin therapy was administered in therapeutic dose. A control ultrasound examination revealed no features of thrombosis or valvular insufficiency. Despite antibiotic treatment further high inflammation parameters were still noted (CRP 149.4 mg/l), thus further diagnosis for atypical infection was performed (the direct examination of synovial fluid for tuberculosis and in vitro QuantiFERON test, anti - Borrelia burgdorferi antibodies in class IgM and IgG – all negative). After failure of treatment and the patient’s continuing complaints, the patient was referred to the Department of Rheumatology.
At the time of admission to the Department of Rheumatology the patient reported left knee pain sustained for more than a month and lumbar spine pain, severity independent of physical exercise, exacerbating during the night and accompanied by morning stiffness. Joint mobility within the normal range, soreness during loading and maximum limbs bent. In addition, Patrick sign was positive on the left side. After more detailed anamnesis the patient confirmed occurrence of typical inflammatory back pain of nearly 20 years. The pain typically worsened with inactivity and improved with exercise and non-steroid anti-inflammatory drugs (NSAIDs) treatment. Morning stiffness was prolonged to nearly all day. Nocturnal pain was not awakening her. The patient’s spine motion was markedly limited in all directions: Otto’s test 2 cm, Schober’s test 1.5 cm, chest expansion 3.5 cm deepening the cervical lordosis. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 6.2 whereas Bath Ankylosing Spondylitis Functional Index (BASFI) 2.5. There was neither edema nor mobility limitations in other peripheral joints. No other significant deviations from the norm in the rest of physical examination were noted. The symptoms were accompanied by high erythrocyte sedimentation rate (ESR) 98 mm/h, CRP 119.8 mg/l following an increase of creatinine concentration up to 144 μmol/l (GFRCKD-EPI 35.7 ml/min/1.73m2).
During hospitalization the antibiotic therapy started in the Department of Nephrology was completed, whilst the anti-coagulant therapy was continued. An x-ray of the lumbar spine and of the targeted sacroiliac joints revealed lesions characteristic of ankylosing spondylitis: vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints (Fig. 1). The patient was HLA B27 positive, autoantibodies like the antinuclear antibodies (ANA), anti- cyclic citrullinated peptides antibodies and rheumatoid factor were negative. After the negative result of control culture of the synovial fluid, intrarticular injection of bethametazone and lignocaine mixture was administered. The fluid fulfilled the criteria for the inflammatory fluid type I (Table 1). Uric acid crystals were not detected. The NMR of the lumbar spine done in the Nephrology Unit was assessed once again by a more experienced radiologist in the Rheumatology Unit and was described as typical features of ankylosing spondylitis. A diagnosis of ankylosing spondylitis was posed (Tables 2 and 3) and the patient was started on oral sulphasalazine and NSAIDs. The treatment resulted in a significant decrease of CRP and improvement of the graft function (sCr 92 μmol/l, eGFR 61.4 ml/min/1.73 m2). The diagnosis of chronic kidney disease (CKD) and KTx determined a reduction of sulphasalazine dose to 2x500mg and after a short therapy the NSAIDs administration was reduced. Radiosynovectomy in the left knee joint was performed and after 2 weeks the patient, in good general condition, was discharged home.
Fig. 1 X-ray revealed diffuse syndesmophyitic ankylosis at all levels from Th12 to L1 (also seen above Th12), calcifications of spinal ligaments, features of vertebral body squaring, radiological signs of spondylodiscitis at levels from L1 to L4 with the widening of intervertebral space, blurring the trabecular structure of L5 and L6 narrowing of intervertebral spaces L4-S1. Left site scoliosis
Table 1 Synovial fluid parameters
Synovial fluid parameters
Volume 60 ml
Colour Yellow
Clarity Transparent
Viscosity High
Total protein 50.3 g/l
Glucose level Lower than blood
WBC 800/mm3
PMNs > 50%
Culture Negative
Table 2 Amor diagnostic criteria for spondyloarthropathy
Amor Criteria Our patient
Inflammatory back pain 1 point +
Unilateral buttock pain 1 point –
Alternating buttock pain 2 point –
Enthesitis 2 point +/−
Peripheral arthritis 2 point +
Dactylitis (sausage digit) 2 point –
Acute anterior uveitis 2 point –
HLA-B27
–positive or family history of spondyloarthropathy 2 point +
Good response to NSAIDs 2 point +
Diagnosis of spondyloarthropathy with 6 or more points 7–9 points
Table 3 New York diagnostic criteria for spondyloarthropathy
New York Criteria Our patient
Low back pain with inflammatory characteristics +
Limitation of lumbar spine motion in sagittal and frontal planes +
Decreased chest expansion +
Bilateral sacroiliitis grade 2 or higher +
Unilateral sacroiliitis grade 3 or higher
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria 4 points
After 6 years of follow up during the routine visits in out-patient Transplantation Department the patient does not present any complaints associated with the left knee (no pain, tenderness, oedema). The graft function is still stable – creatinine concentration 90 μmol/l, GFRCKD-EPI 62 ml/min/1.73m2, she has been treated long-term with her base immunosuppressive therapy (stable dose of CsA 75 mg bid, stable dose of MMF 500 mg bid, and temporarily, increased steroid dose up to 20 mg qd at the moment of AS diagnosis with the subsequent dose reduction to 5 mg qd), with reduced sulphasalazine dose (2 × 500 mg), with no adverse effects of such treatment.
Discussion and conclusion
Joint pain is a frequent problem in individuals with kidney disease and is common both before and after KTx [11]. However, kidney involvement can be one of the complications following rheumatic diseases and can occur as a secondary amyloidosis which is the most common cause of nephrotic syndrome in AS followed by IgA nephropathy, mesangioproliferative glomerulonephritis as well as, rarely, by membranous nephropathy or focal segmental glomerulosclerosis [10]. A study by Hill et al. showed an 18% prevalence of CKD stages 3 to 5 in the rheumatic outpatient group, as compared to 5% reported within the general population [12]. On the other hand, it was shown that rheumatic diseases were the cause of ESRD and KTx in 14% of recipients transplanted in Poland between 1998 and 2015 years [13]. The authors showed that patients and graft survival were distinctly better in nonrheumatic recipients in comparison with rheumatic patients [13].
Differential diagnosis of joint and back pain in patients after successful KTx should take into account common complications of dialysis including crystal deposition disease, β2- microglobulin amyloidosis, secondary hyperparathyroidism, or aluminium overload as well as articular complications followed by hepatitis B and C or a variety of other infections [14]. In KTx recipients some new musculoskeletal and articular disorders, like infection-related arthralgia, polyarticular gout, rheumatoid arthritis flare, or a medication-related adverse reaction, namely steroid induced osteopenia or osteoporosis, may occur [11].
To the best of our knowledge, the present work is the first case report of late onset of seronegative spondyloarthropathy in a transplanted patient despite ongoing immunosuppressive treatment. De novo seropositive erosive rheumatoid arthritis in a patient 7 years after KTx was described by Forslund et al. in 2005 [15].
Immunosuppressive treatment after transplantation on the one hand prevents rejection of the transplanted organ, and on the other hand is an excellent treatment for diseases of the autoimmune and inflammatory background, preventing an exaggerated immune response. However certain injuries may alter this balance leading to dysregulation of the intestinal immune environment promoting the development of chronic inflammatory disease [16]. Immunosuppression heightens susceptibility to infectious agents that may damage the epithelial barrier of the intestinal mucosa resulting in prolonged exposure to luminal antigens followed by chronic immune stimulation [16].
Calcineurin inhibitors including CsA and tacrolimus strongly inhibit production of interleukin-2 (IL-2), which is normally produced by T cells to induce expansion of antigen-specific clones in response to a previously encountered antigen. Deficiency of IL-2 can result in T-cell dysregulation, leading to the development of chronic inflammation [17]. Arthralgia, muscular side effects and osteoarthropathy are some of the described side effects of CsA associated therapy. It was shown that high CsA levels (> 200 ng/ml) are the risk factors of joint pain in KTx recipients [11]. Our patient had the CsA trough level low, appropriate to time passed after KTx.
It has been found that mycophenolate mofetil can be associated with an acute inflammatory response characterized by fever, arthralgia, oligoarthritis and raised inflammatory markers appearing 3 to 5 days after initiation of therapy with MMF. Symptoms rapidly resolve with mycophenolate cessation. The pathogenesis has been associated with paradoxical pro-inflammatory reaction of polymorphonuclear neutrophils [18]. Our patient was treated with MMF for years, thus it is unlikely to have been the cause of symptoms.
The appearance of inflammatory disease regardless of adequate immunosuppressive therapy in transplant recipients is not unusual or impossible, however there is no data available associated with new onset of AS after transplantation. Moreover the most typical risk group of AS are young men, whereas the presented patient is a 58 year old woman. Very rarely does AS begin after the age of 40 resulting in difficulties in making the diagnosis, since standard classification scales are not validated for patients above 45 years old [19, 20].
The diagnosis of arthritis is primarily clinical. The most typical clinical features of arthritis of native joints are acute joint pain, swelling, warmth, erythema, decreased range of motion, fever, and general malaise. AS is characterised by the presence of spinal pain, resulting in limitation of spinal mobility reported also by our patient. These symptoms can be supported by laboratory evidence like leukocytosis or inflammatory markers including CRP, procalcitonin and ESR, which can be useful especially in patients with native joints without underlying haematological or rheumatological conditions. However, all of these laboratory tests have quite low sensitivity and specificity. Laboratory tests are usually followed by X-ray, ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI) of the involved joint. To diagnose joint infection aspiration of the joints can be performed, however mainly in large joints.
As written above the immunosuppressive treatment can be associated with increased risk of infectious diseases. Therefore, the most common cause of monoarticular arthritis in both immunocompetent and immunocompromised patients is septic arthritis [21]. Symptoms of AS (low back pain) were reported by our patient for 20 years, but as low back pain is a common condition and the patient did not present other features of spondyloarthropathy like enthesitis, dactylitis, uveitis, diarrhoea or family clustering, the patient was not referred to a rheumatologist and the complaints were described as non-specific, mechanical low back pain. It cannot be excluded that the symptoms of AS were present earlier but were masked by anti-inflammatory properties of immunosuppressive drugs.
Although most cases of viral and reactive arthritis are connected with infectious background, they are usually not categorized as septic arthritis [21]. Monoarticular arthritis can result from viral infection caused by parvovirus B19, HIV or rubella, as well as from the deposition of immune complexes and complement components in hepatitis B and C infections [19]. In our patient the viral infections were excluded.
Reactive arthritis usually arises from an acute infection of the genitourinary or gastrointestinal tract caused by Shigella spp., Salmonella spp., Campylobacter jejuni, or Yersinia enterocolitica. It may also be one of the manifestations of Lyme disease [21, 22].
In the traditional understanding of septic arthritis the most commonly implicated organisms causing bacteremic septic arthritis are Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Neisseria gonorrhoeae, Klebsiella pneumonia, Escherichia coli, Proteus spp., Salmonella spp., Morganella morganii, Citrobacter spp., Serratias spp or Pseudomonas aerginosa [22–24]. Septic arthritis can also result from mycobacteria (Mycobacterium tuberculosis), or fungi infections (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) [21].
The most common predisposing factors for septic arthritis include age greater than 80 years, diabetes mellitus, rheumatoid arthritis, prosthetic joint, recent joint surgery, skin infection and skin ulcers, intravenous drug abuse and alcoholism, and previous intra-articular corticosteroid administration [25].
Transplant patients are particularly susceptible to develop septic arthritis caused by unusual organisms. These infections are commonly disseminated, involving both the bones and joints [25]. In the first few weeks after transplantation, joint infections are often hematogenous and caused by health-care-associated pathogens such as Staphylococcus aureus (including MRSA) and gram-negative bacilli like Pseudomonas aeruginosa [26]. However, in the months following transplantation, as patients are maintained on immunosuppressive therapy, they are more prone to infections caused by fungi and mycobacteria [26]. In our recipients fungi and mycobacteria were excluded.
Gout etiology was thought unlikely in our patient as no crystals were present on joint aspirate and the patient had no history of gout, with only slight elevated serum uric acid concentration [19] – thus this diagnosis was excluded in our case.
Following the modified New York criteria for AS it has been shown that radiographic sacroilitis is a rather late finding in the disease course of many patients [3]. The most typical radiological evidence for AS are structural changes in the sacroiliac joints and the spine. In our patient the typical features like vertebral body squaring, diffuse syndesmophyitic ankyloses giving a “bamboo spine” appearance and total ankyloses of sacroiliac joints were described on X-ray, whereas MRI revealed nothing specific.
Progression of AS varies among individuals, but some general trends can be observed. Younger age (≤40 years) at disease onset is usually associated with a predominance of axial symptoms, whereas patients with a later disease onset tend to present more peripheral manifestations [9]. Symptoms presented by our patient were associated with the spinal column despite her belonging to an older group.
The main purpose of treating the patient with AS is to improve long-term health-related quality of life by controlling the symptoms of the disease and averting continuous structural damage, thus leading to better joint function followed by improved social participation [3]. The treatment of AS should be personalised according to the present symptoms of the disease, patient’s comorbidities, possible complications resulting from the treatment and psychosocial factors [3].
The first-line drug treatment for patients complaining of pain and stiffness are NSAIDs administered up to the maximum dose, taking into consideration risks and benefits resulting from the treatment [27, 28]. Data from some studies revealed that in young patients failure to administered NSAIDs is associated with an increased mortality [29, 30]. For patients with good response to NSAIDs continuous use is recommended [3]. This first-line treatment should be enhanced by physical therapy including home exercises and by smoking cessation [31]. In patients who are contraindicated to NSAIDs or poorly tolerate this treatment, analgesics such as paracetamol and opioid-(like) drugs should be considered [3].
Lack of efficacy or presence of toxicity with NSAIDs is an indication to consider alternative treatments either with glucocorticoid, sulfasalazine or biological disease-modifying antirheumatic drugs (bDMARDs) [3].
Steroid injections directed to the local site of musculoskeletal inflammation may be recommended in patients with predominant peripheral manifestation as an option to treat arthritis and enthesitis, although direct evidence is lacking. Patients with axial disease should not be treated with systemic glucocorticoids for a long time [3].
Sulfasalazine may be considered in patients with peripheral arthritis, however it does not alleviate axial symptoms [32].
High disease activity defined as BASDAI ≥4 despite conventional treatment, elevated CRP, presence of inflammation on MRI of the SI joints and/or spine or presence of radiographic sacroiliitis is an indication to start bDMARDs and current practice is to start with tumour necrosis factor inhibitor (TNFi) therapy [31].
Our patient due to KTx was put on immunosuppressive therapy including CsA, MMF and steroids. Given the ongoing severity of the patient’s symptoms, no response to maintenance immunosuppressive therapy, contraindication to NSAIDs, a change in management was instituted by the administration of sulfasalazine. Improvement in the patient’s inflammatory markers and arthritis was noticed with subsidence of pain complaints and normalization of CRP within 2 weeks. She has had no further recurrence of acute inflammatory arthritis.
The establishing of proper diagnosis and management of a patient after KTx is difficult. Despite long-term immunosuppressive treatment in solid organ transplant recipients, in the differential diagnosis of joint pain the development of de novo arthritis should be considered, and when conclusive diagnosis is made, the patient may require administration of additional immunosuppressive drugs.
Abbreviations
ANAAntinuclear antibodies
anti-CCPAnti- cyclic citrullinated peptides
ASAnkylosing spondylitis
BASDAIBath Ankylosing Spondylitis Disease Activity Index
BASFIBath Ankylosing Spondylitis Functional Index
bDMARDsBiological disease-modifying antirheumatic drugs
CKDChronic kidney disease
CRPC-reactive protein
CsACyclosporine A
CTComputer tomography
eGFREstimated glomerular filtration rate
ESRErythrocyte sedimentation rate
ESRDEnd-stage renal disease
HPFHigher-power field
KtxKidney transplantation
MMFMycophenolate mofetil
MRIMagnetic resonance imaging
NMRNuclear magnetic resonance
NSAIDsNon-steroid anti-inflammatory drugs
SCrSerum creatinine concentration
TNFiTumour necrosis factor inhibitor
WBCWhite blood count
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Acknowledgements
Not applicable.
Authors’ contributions
All authors have read and have approved the submitted version of the manuscript. AZB: designed the case report plan, described the subject medical history and was the primary author for the manuscript; OB: helped design the case report plan, IK helped in writing the manuscript, JM helped in writing the manuscript. All authors have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.
Funding
Not applicable.
Availability of data and materials
The patient results used and/or analysed during the current case report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable (case report).
Consent for publication
The patient in written consent agreed to publish the laboratory as well as radiological results.
Competing interests
None of the authors claims a conflict of interest. All authors declare no financial and non-financial competing interests. | Recovered | ReactionOutcome | CC BY | 33517879 | 19,003,793 | 2021-01-31 |
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