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What was the dosage of drug 'GEMCITABINE'? | Pancreaticoduodenectomy combined with splenectomy for a patient with pancreatic cancer and pancytopenia due to liver cirrhosis: Case report.
The incidence of patients with liver cirrhosis (LC) is increasing. Patients with LC are known to have a greater risk of postoperative morbidity and mortality than patients without LC. A treatment option such as pancreaticoduodenectomy (PD) has not been validated to be safe for these patients, especially those with pancytopenia due to portal hypertension (PH). Providing an effective treatment option for these patients is essential.
METHODS
Herein, we describe a patient with pancreatic cancer with pancytopenia due to LC that was successfully treated with PD combined with splenectomy. The patient was a 70-year-old woman who was referred to our hospital for evaluation of a mass in the pancreatic head after she developed obstructive jaundice. She was diagnosed with T2N0M0, Stage IB pancreatic cancer and pancytopenia due to PH associated with LC. She received 2 cycles of adjuvant gemcitabine/S-1 chemotherapy and underwent radical subtotal stomach-preserving pancreaticoduodenectomy with splenectomy to improve her pancytopenia. Histopathological examination of the resected specimen revealed an R0 resection showing an Evans grade IIa histological response. Her pancytopenia improved rapidly after surgery.
Strict indications for PD, haemostatic control of intraoperative bleeding, and optimal perioperative management were important for preventing hepatic decompensation in this patient. Splenectomy is effective for thrombocytopenia due to LC; however, attention to postoperative complications such as overwhelming post-splenectomy infection and portal vein thrombosis is required.
CONCLUSIONS
For patients with pancreatic cancer with pancytopenia due to LC, PD combined with splenectomy plus optimal perioperative management is effective.
1 Introduction
Patients with liver cirrhosis (LC) have been recognized to have a greater risk of postoperative morbidity and mortality than patients without LC [1,2]. The safety of pancreaticoduodenectomy (PD) for patients with chronic hepatic dysfunction due to LC has not been validated. The risk of pancreaticoduodenectomy (PD) for patients increases with the progression of LC, because of the development of pancytopenia due to portal hypertension (PH) and secondary hypersplenism.
Perioperative chemotherapy has played an increasingly important role in the treatment of patients with pancreatic cancer (PC). Therefore, it is important to provide appropriate treatment options, including chemotherapy, for a patient with PC and pancytopenia due to LC. Herein we describe a patient with PC with pancytopenia due to LC who was successfully treated by PD combined with splenectomy, which enabled the safe postoperative administration of chemotherapy. We report this case in accordance with the 2020 SCARE criteria [3].
2 Case report
A 70-year-old woman with obstructive jaundice underwent percutaneous transhepatic biliary drainage instead of endoscopic biliary drainage because of her duodenal stenosis. She was then referred to our hospital for evaluation of a pancreatic head lesion that had been identified on an abdominal computed tomography (CT) scan performed when her jaundice had been discovered. She had a past history of endovascular aneurysmal repair (EVAR) for an abdominal aortic aneurysm one year previously and an appendectomy followed by surgery for an ileus when she was 10 years of age. Her family history was negative for pancreatic cancer and genetic disorders. She was 151 cm tall and weighed 60 kg. Her body-mass index was 26.3. The results of her physical examination were unremarkable.
Laboratory analysis revealed pancytopenia (white blood cell count 2710/μL, red blood cell count 366 × 104/μL, haemoglobin 10.9 g/dL, platelet count 89 × 103/μL) and CA19−9 3909 U/mL). She was negative for hepatitis B surface antigen and anti-hepatitis C virus antibody. Her Child-Pugh score and Model for End-stage Liver Disease (MELD) score were Grade 5A and 9, respectively [[4], [5], [6]]. Enhanced multidetector-row computed tomography (CT) revealed a 25-mm hypovascular tumour in the pancreatic groove, which had invaded the duodenum and lower bile duct (Fig. 1a). No other metastases involving distant organs were seen. Dullness of the hepatic margins was observed, and the spleen appeared enlarged, with a maximum diameter of 15 cm, suggesting portal hypertension (PH) (Fig. 1b). Endoscopic ultrasound-guided fine needle aspiration was performed. The cytopathological findings revealed pancreatic adenocarcinoma. Based on the 8th edition of the UICC criteria, the findings were diagnosed to be T2N0M0, Stage IB pancreatic carcinoma.Fig. 1 Pretreatment coronal enhanced computed tomography images.
a) Hypovascular 25-mm tumour (white arrow) in the pancreatic groove invading the duodenum and lower bile duct.
b) Splenomegaly with a maximum splenic diameter of 15 cm, which suggests portal hypertension.
Fig. 1
In accordance with the findings of the phase 2/3 Prep-02/JSAP05 trial [7], the patient underwent neoadjuvant gemcitabine/S-1 (GS) chemotherapy (gemcitabine [800 mg/m2] on days 1, 8 and S-1 [100 mg/m2] on days 1–14 of a 21-day cycle) repeated every 3 weeks for 2 cycles. Because of the patient’s pretreatment pancytopenia (neutrophil count 2250/μL), gemcitabine and S-1 were reduced by 200 mg/m2/day to 800 mg/m2/day, and 20 mg/m2/day to 100 mg/m2/day, respectively. Even after the dose reduction, neutropenia (neutrophil count 1340/μL) was observed during 1 cycle of GS, and chemotherapy was withheld until the neutropenia was resolved. Although the patient’s serum CA 19−9 level decreased after 2 cycles of GS chemotherapy, it remained elevated (CA 19−9 1064 U/mL). After 2 cycles, the primary tumour had slightly decreased to a diameter of 24 mm. Since the level of her CA19−9 tumour marker remained elevated, her risk of postoperative recurrence after PD was high. However, if the tumour recurred, the administration of intensive chemotherapy such as FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel regimens would be difficult because of the patient’s pancytopenia. Therefore, we elected to perform a splenectomy in addition to the PD to improve her pancytopenia.
Splenectomy for splenomegaly with PH occasionally results in loss of a large amount of blood, which requires a large transfusion. The transfusion leads to oedema of the intestinal wall, which can increase the difficulty of performing a PD. Therefore, we decided to perform the PD followed by splenectomy.
The intraoperative findings revealed a liver with a granular surface and dullness of the liver’s edge (Fig. 2). We performed extensive detachment of the adhesions due to the patient’s previous appendectomy and subsequent surgery for an ileus, and found that detaching the hepatoduodenal ligament was difficult because of her repeated preoperative episodes of cholangitis. Since the collateral hepatic circulation that had developed bled easily, haemostasis was performed safely by ligation. After the PD, we began the splenectomy. We first detached and ligated the splenic artery (SA) at the upper edge of the pancreatic body to shrink the spleen and reduce the amount of blood loss. The splenic vein (SV) was also ligated, but the splenic hilum bled heavily because of tension on the SV. Haemostasis was performed by ligation while elevating the splenic hilum from the dorsal side. Finally, we performed a radical subtotal stomach-preserving PD with splenectomy, and lymph node dissections of groups 1 and 2 that included the hepatoduodenal ligament caudal to the hilar plate. The operative time was 12 h and 7 min, and the volume of blood loss was 1990 mL.Fig. 2 Intraoperative image.
Intraoperative findings show the dullness of the liver’s edge and its granular surface.
Fig. 2
The excised specimens showed a solid tumour in the pancreatic head which had invaded the duodenum and bile duct (Fig. 3a), and splenomegaly (Fig. 3b). The histopathological diagnosis was invasive ductal carcinoma with severe venous invasion and moderate nerve infiltration, ypT2N0M0, ypStage IB pancreatic cancer, as based on the 8th Edition of the UICC criteria and grade IIa as based on the Evans classification [8] (Fig. 4).Fig. 3 Macroscopic views of the resected specimens.
a) Macroscopic image of the resected specimen shows a mass in the pancreatic head, which has invaded the duodenum and bile duct.
b) The resected spleen is enlarged.
Fig. 3
Fig. 4 Photomicrograph (haematoxylin-and-eosin stain).
Malignant cells (arrows) have invaded the bile ducts (arrowheads).
Fig. 4
The patient’s pancytopenia improved rapidly after surgery. The platelet count increased rapidly after splenectomy, peaking at 681,000/μL on postoperative day (POD) 16, and then decreasing to the normal range (Fig. 5). However, the patient developed atelectasis and splenic vein thrombosis, which were considered Grade II complications in accordance with the Clavien-Dindo classification. The patient received high-flow nasal oxygen therapy and noninvasive positive-pressure ventilation, including bilevel positive airway pressure, and was prescribed an anticoagulant agent for the thrombosis. The patient was moved out of the intensive care unit on POD 5, and discharged on POD 30. After having received adjuvant chemotherapy with S-1 for 2 months due to the anorexia, the patient underwent blood tests and CT scans every 3 months. Nine months after her PD, a liver metastasis was detected, for which she received chemotherapy. She has remained alive for 13 months after her PD.Fig. 5 Graph of platelet and white blood cell counts over the patient’s hospital course.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy
Adjuvant S-1: Adjuvant S-1 chemotherapy
Fig. 5
3 Discussion
The outcomes of surgery in patients with LC have been reported to vary, based not only on the degree of damage to the liver but also the invasiveness of the surgery [9]. The reported mortality of major abdominal surgery for patients with LC is 35% [10]. The Child-Pugh classification and the MELD score have been useful for estimating the risk of surgical mortality. According to the Child-Pugh classification, the mortality rates for major abdominal surgery have been 10%, 30%, and 76%–82% for Child-Pugh classifications A, B, and C, respectively [11]. Whereas, according to the MELD score, the 30-day mortalities after surgery were reported to be 6% for MELD < 8 and 50% for MELD > 20 [12]. However, until now, to our best knowledge, only a few studies have been published on the outcomes of PD in patients with LC. A retrospective multicentre study reported that PH and a serum aspartate aminotransferase (AST) of <50 IU/L were significant independent risk factors for hepatic decompensation, and an AST of < 50 IU/L and an AST-to-platelet-ratio index (APRI) ≥ 1.0 for a patient with a Child-Pugh B classification may be indications that PD can be performed [13]. At the first visit, our patient’s AST value, APRI value, and Child-Pugh score were 57 IU/L, 1.6, and 5A, respectively. After 2 cycles of GS, her preoperative AST and APRI values had decreased to 22 IU/L and 0.5, respectively. Therefore, our patient had appropriate indications for undergoing a PD. Her postoperative Child-Pugh score has remained 5–6 (Class A), with no increase in the APRI (Table 1). The increase in the postoperative MELD score was considered to be due to her anorexia associated with S1 adjuvant chemotherapy.Table 1 Table of perioperative Child-Pugh and MELD scores and APRI score.
Table 1 Pre-treatment After 2 cycles of GS POM1 POM2 POM3 POM4 POM5 POM6
Child-Pugh score 5 5 5 5 5 6 6 5
MELD score 9 3 1 0 1 3 5 3
APRI 1.6 0.5 0.2 0.1 0.1 0.1 0.1 0.1
APRI: AST-to-platelet-ratio index.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy.
POM: Postoperative month.
Pancytopenia has a wide range of aetiologies, including malignancies (leukaemia, malignant lymphoma, myelodysplastic syndrome, myeloma), autoimmune conditions (aplastic anaemia, systemic lupus erythematosus [SLE]), hypersplenism due to LC, drugs, infections, and nutritional deficiencies, so the evaluation of a patient with pancytopenia requires a comprehensive approach [14]. Regarding the patient’s thrombocytopenia, the causes of thrombocytopenia often overlap with the causes of pancytopenia [15]. Because our patient did not have lymphadenopathy, SLE, recent extensive thrombosis, blasts or atypical cells at peripheral blood tests, abnormal findings in her bone marrow, abnormal lymph nodes on CT or PET-CT, signs of infection, recent changes in oral medication, or a history of gastrectomy, we excluded malignancies, autoimmune conditions, drug reactions, infections, and nutritional deficiencies from the differential diagnosis. CT showed dullness of the hepatic margins, splenomegaly, and presence of a collateral circulation; we concluded that her pancytopenia, including her thrombocytopenia, was caused by hypersplenism due to LC. Therefore, we did not think that a bone-marrow biopsy was a priority, compared with preoperative chemotherapy for pancreatic cancer.
Thrombocytopenia (platelet count < 150,000/μL) [16] can occur with the progression of LC. The production of thrombopoietin and sequestration of platelets in the spleen are the main mechanisms involved in the development of thrombocytopenia [17]. The treatments for thrombocytopenia due to LC have included platelet transfusions, medications, embolization of the SA, and splenectomy [18]. With our patient’s elevated CA19−9 level, the risk of recurrence of her pancreatic cancer was considered high, and we elected to add treatment for improving her pancytopenia in order to enable the safe administration of chemotherapy after her recurrence. Platelet transfusion was not performed because of her splenomegaly and because of the possibility of platelet sequestration followed by destruction. We did not administer a thrombopoietin receptor agonist such as eltrombopag, which is effective for thrombocytopenia, because the patient required treatment not only for her thrombocytopenia but also for her pancytopenia. Whether a partial splenic artery embolization (PSAE) or splenectomy should have been performed has been controversial. The complications of PSAE include peritonitis, splenic abscess, and portal vein thrombosis. Additionally, PSAE is an invasive procedure, with both significant cost and uncertain long-term benefits. These limitations make PSAE an unsuitable option for many patients with advanced LC [17]. Furthermore, Miyake et al. reported that platelet counts after splenectomy were significantly increased over platelet counts after PSAE [19]. On the other hand, although splenectomy is an effective option for improving pancytopenia, it is also invasive and occasionally results in massive loss of blood. Additionally, the main complications after splenectomy are overwhelming post-splenectomy infections (OPSIs), approximately 80% of which are pneumococcal, and portal vein thrombosis. The reported incidence of portal vein thrombosis after splenectomy for splenomegaly has ranged from 9% to 29% [17].
For our patient, we debated about performing a splenectomy. Ligation or embolization of the SA was also considered, but we considered the effect of those procedures to be limited, because the blood supply of the spleen was delivered via collateral circulation, including the left gastric artery, the stomach wall, and the middle colic artery [20,21]. Therefore, we decided to perform a splenectomy, which seemed to provide the most reliable effect of increasing the blood cell count for the chemotherapy after recurrence of pancreatic cancer [19]. After confirmation that there were no distant metastases after neoadjuvant chemotherapy, we finally performed a radical PD combined with splenectomy following the approval by a multidisciplinary team a few days before the surgery. The patient also received postoperative pneumococcal vaccine to prevent OPSI before she underwent chemotherapy. However, the vaccine should have been administered before surgery in this high-risk patient.
With regard to preoperative chemotherapy, Karl et al. reported the usefulness and low toxicity of chemotherapy administered by intra-arterial infusion, including isolated abdominal perfusion [22]. However, our patient also had an abdominal aortic aneurysm with type 2 endoleak despite her previous EVAR, so catheterization was considered to be difficult. Additionally, her pretreatment CA19−9 level was very high (CA19−9 3909 U/mL), suggesting the possibility of micrometastases. Therefore, we elected to perform dose-reduced systemic chemotherapy for the early treatment and suppression of micrometastatic disease.
To our best knowledge, when limited to cases of PD synchronous with splenectomy for PC with pancytopenia due to LC, a total of 2 cases have been reported, including our case [23]. As in our patient, who lost a large volume of blood, Futagawa et al. reported a large blood loss (1700 mL). In patients with LC, bleeding occurs readily because of PH and decreased coagulability, and there is concern that hepatic function may deteriorate because of blood transfusions. Therefore, the control of intraoperative bleeding by reliable haemostasis is important. Furthermore, in patients with PH in whom collateral circulation develops, attention must be paid to the extent of lymph node dissection. Dissection of the hepatoduodenal ligament interrupts the collateral circulation, which can lead to refractory ascites and hepatic decompensation. Group 1 and 2 lymph node dissections were performed for our patient, who did not develop hepatic decompensation. However, careful planning that takes into consideration a patient’s overall condition and degree of liver damage is needed before surgery for these patients.
When PD is performed for a patient with LC, prevention of hepatic decompensation, which is directly is associated with mortality, is the most important consideration. Optimal perioperative management may decrease morbidity and mortality following surgery. Perioperative management for patients with LC includes nutritional management, control of refractory ascites and glucose levels, and correction of coagulopathy. These measures can help in preventing infection, hepatic encephalopathy and hepatic decompensation [24]. In our case, enteral nutrition therapy was started immediately after surgery for nutritional management and the prevention of postoperative infections [25]. In addition, since patients with LC who undergo PD, which is a highly invasive procedure, have increased risk of postoperative morbidity and mortality, careful monitoring and follow up are essential.
4 Conclusions
Strict indications for PD, control of intraoperative bleeding, and optimal perioperative management are important for preventing hepatic decompensation. Even for patients with PC and pancytopenia due to LC, PD combined with splenectomy is an effective treatment option.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Funding
This study did not receive any specific grants from funding agencies in the public, commercial, and not-for-profit sectors.
Ethical approval
This study was exempt from ethical approval at our institution.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
HT (certified by the Japanese Society of Gastroenterological Surgery) performed the surgery on this patient. IH, HT, KM, and TH managed the postoperative course of this patient. HT and HI wrote the manuscript. All authors have read and approved the final manuscript.
Registration of research studies
Not Applicable.
Guarantor
Hideharu Tanaka (Corresponding author and guarantor).
Provenance and peer review
Not commissioned, externally peer-reviewed.
Availability of data and materials
Not applicable.
Acknowledgements
The authors wish to thank JAM Post for the editing of a draft of this manuscript. | 800 MILLIGRAM/SQ. METER ON DAYS 1, 8; REPEATED EVERY 3WEEKS FOR 2 CYCLES | DrugDosageText | CC BY | 33689973 | 19,088,732 | 2021-04 |
What was the dosage of drug 'GIMERACIL\OTERACIL\TEGAFUR'? | Pancreaticoduodenectomy combined with splenectomy for a patient with pancreatic cancer and pancytopenia due to liver cirrhosis: Case report.
The incidence of patients with liver cirrhosis (LC) is increasing. Patients with LC are known to have a greater risk of postoperative morbidity and mortality than patients without LC. A treatment option such as pancreaticoduodenectomy (PD) has not been validated to be safe for these patients, especially those with pancytopenia due to portal hypertension (PH). Providing an effective treatment option for these patients is essential.
METHODS
Herein, we describe a patient with pancreatic cancer with pancytopenia due to LC that was successfully treated with PD combined with splenectomy. The patient was a 70-year-old woman who was referred to our hospital for evaluation of a mass in the pancreatic head after she developed obstructive jaundice. She was diagnosed with T2N0M0, Stage IB pancreatic cancer and pancytopenia due to PH associated with LC. She received 2 cycles of adjuvant gemcitabine/S-1 chemotherapy and underwent radical subtotal stomach-preserving pancreaticoduodenectomy with splenectomy to improve her pancytopenia. Histopathological examination of the resected specimen revealed an R0 resection showing an Evans grade IIa histological response. Her pancytopenia improved rapidly after surgery.
Strict indications for PD, haemostatic control of intraoperative bleeding, and optimal perioperative management were important for preventing hepatic decompensation in this patient. Splenectomy is effective for thrombocytopenia due to LC; however, attention to postoperative complications such as overwhelming post-splenectomy infection and portal vein thrombosis is required.
CONCLUSIONS
For patients with pancreatic cancer with pancytopenia due to LC, PD combined with splenectomy plus optimal perioperative management is effective.
1 Introduction
Patients with liver cirrhosis (LC) have been recognized to have a greater risk of postoperative morbidity and mortality than patients without LC [1,2]. The safety of pancreaticoduodenectomy (PD) for patients with chronic hepatic dysfunction due to LC has not been validated. The risk of pancreaticoduodenectomy (PD) for patients increases with the progression of LC, because of the development of pancytopenia due to portal hypertension (PH) and secondary hypersplenism.
Perioperative chemotherapy has played an increasingly important role in the treatment of patients with pancreatic cancer (PC). Therefore, it is important to provide appropriate treatment options, including chemotherapy, for a patient with PC and pancytopenia due to LC. Herein we describe a patient with PC with pancytopenia due to LC who was successfully treated by PD combined with splenectomy, which enabled the safe postoperative administration of chemotherapy. We report this case in accordance with the 2020 SCARE criteria [3].
2 Case report
A 70-year-old woman with obstructive jaundice underwent percutaneous transhepatic biliary drainage instead of endoscopic biliary drainage because of her duodenal stenosis. She was then referred to our hospital for evaluation of a pancreatic head lesion that had been identified on an abdominal computed tomography (CT) scan performed when her jaundice had been discovered. She had a past history of endovascular aneurysmal repair (EVAR) for an abdominal aortic aneurysm one year previously and an appendectomy followed by surgery for an ileus when she was 10 years of age. Her family history was negative for pancreatic cancer and genetic disorders. She was 151 cm tall and weighed 60 kg. Her body-mass index was 26.3. The results of her physical examination were unremarkable.
Laboratory analysis revealed pancytopenia (white blood cell count 2710/μL, red blood cell count 366 × 104/μL, haemoglobin 10.9 g/dL, platelet count 89 × 103/μL) and CA19−9 3909 U/mL). She was negative for hepatitis B surface antigen and anti-hepatitis C virus antibody. Her Child-Pugh score and Model for End-stage Liver Disease (MELD) score were Grade 5A and 9, respectively [[4], [5], [6]]. Enhanced multidetector-row computed tomography (CT) revealed a 25-mm hypovascular tumour in the pancreatic groove, which had invaded the duodenum and lower bile duct (Fig. 1a). No other metastases involving distant organs were seen. Dullness of the hepatic margins was observed, and the spleen appeared enlarged, with a maximum diameter of 15 cm, suggesting portal hypertension (PH) (Fig. 1b). Endoscopic ultrasound-guided fine needle aspiration was performed. The cytopathological findings revealed pancreatic adenocarcinoma. Based on the 8th edition of the UICC criteria, the findings were diagnosed to be T2N0M0, Stage IB pancreatic carcinoma.Fig. 1 Pretreatment coronal enhanced computed tomography images.
a) Hypovascular 25-mm tumour (white arrow) in the pancreatic groove invading the duodenum and lower bile duct.
b) Splenomegaly with a maximum splenic diameter of 15 cm, which suggests portal hypertension.
Fig. 1
In accordance with the findings of the phase 2/3 Prep-02/JSAP05 trial [7], the patient underwent neoadjuvant gemcitabine/S-1 (GS) chemotherapy (gemcitabine [800 mg/m2] on days 1, 8 and S-1 [100 mg/m2] on days 1–14 of a 21-day cycle) repeated every 3 weeks for 2 cycles. Because of the patient’s pretreatment pancytopenia (neutrophil count 2250/μL), gemcitabine and S-1 were reduced by 200 mg/m2/day to 800 mg/m2/day, and 20 mg/m2/day to 100 mg/m2/day, respectively. Even after the dose reduction, neutropenia (neutrophil count 1340/μL) was observed during 1 cycle of GS, and chemotherapy was withheld until the neutropenia was resolved. Although the patient’s serum CA 19−9 level decreased after 2 cycles of GS chemotherapy, it remained elevated (CA 19−9 1064 U/mL). After 2 cycles, the primary tumour had slightly decreased to a diameter of 24 mm. Since the level of her CA19−9 tumour marker remained elevated, her risk of postoperative recurrence after PD was high. However, if the tumour recurred, the administration of intensive chemotherapy such as FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel regimens would be difficult because of the patient’s pancytopenia. Therefore, we elected to perform a splenectomy in addition to the PD to improve her pancytopenia.
Splenectomy for splenomegaly with PH occasionally results in loss of a large amount of blood, which requires a large transfusion. The transfusion leads to oedema of the intestinal wall, which can increase the difficulty of performing a PD. Therefore, we decided to perform the PD followed by splenectomy.
The intraoperative findings revealed a liver with a granular surface and dullness of the liver’s edge (Fig. 2). We performed extensive detachment of the adhesions due to the patient’s previous appendectomy and subsequent surgery for an ileus, and found that detaching the hepatoduodenal ligament was difficult because of her repeated preoperative episodes of cholangitis. Since the collateral hepatic circulation that had developed bled easily, haemostasis was performed safely by ligation. After the PD, we began the splenectomy. We first detached and ligated the splenic artery (SA) at the upper edge of the pancreatic body to shrink the spleen and reduce the amount of blood loss. The splenic vein (SV) was also ligated, but the splenic hilum bled heavily because of tension on the SV. Haemostasis was performed by ligation while elevating the splenic hilum from the dorsal side. Finally, we performed a radical subtotal stomach-preserving PD with splenectomy, and lymph node dissections of groups 1 and 2 that included the hepatoduodenal ligament caudal to the hilar plate. The operative time was 12 h and 7 min, and the volume of blood loss was 1990 mL.Fig. 2 Intraoperative image.
Intraoperative findings show the dullness of the liver’s edge and its granular surface.
Fig. 2
The excised specimens showed a solid tumour in the pancreatic head which had invaded the duodenum and bile duct (Fig. 3a), and splenomegaly (Fig. 3b). The histopathological diagnosis was invasive ductal carcinoma with severe venous invasion and moderate nerve infiltration, ypT2N0M0, ypStage IB pancreatic cancer, as based on the 8th Edition of the UICC criteria and grade IIa as based on the Evans classification [8] (Fig. 4).Fig. 3 Macroscopic views of the resected specimens.
a) Macroscopic image of the resected specimen shows a mass in the pancreatic head, which has invaded the duodenum and bile duct.
b) The resected spleen is enlarged.
Fig. 3
Fig. 4 Photomicrograph (haematoxylin-and-eosin stain).
Malignant cells (arrows) have invaded the bile ducts (arrowheads).
Fig. 4
The patient’s pancytopenia improved rapidly after surgery. The platelet count increased rapidly after splenectomy, peaking at 681,000/μL on postoperative day (POD) 16, and then decreasing to the normal range (Fig. 5). However, the patient developed atelectasis and splenic vein thrombosis, which were considered Grade II complications in accordance with the Clavien-Dindo classification. The patient received high-flow nasal oxygen therapy and noninvasive positive-pressure ventilation, including bilevel positive airway pressure, and was prescribed an anticoagulant agent for the thrombosis. The patient was moved out of the intensive care unit on POD 5, and discharged on POD 30. After having received adjuvant chemotherapy with S-1 for 2 months due to the anorexia, the patient underwent blood tests and CT scans every 3 months. Nine months after her PD, a liver metastasis was detected, for which she received chemotherapy. She has remained alive for 13 months after her PD.Fig. 5 Graph of platelet and white blood cell counts over the patient’s hospital course.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy
Adjuvant S-1: Adjuvant S-1 chemotherapy
Fig. 5
3 Discussion
The outcomes of surgery in patients with LC have been reported to vary, based not only on the degree of damage to the liver but also the invasiveness of the surgery [9]. The reported mortality of major abdominal surgery for patients with LC is 35% [10]. The Child-Pugh classification and the MELD score have been useful for estimating the risk of surgical mortality. According to the Child-Pugh classification, the mortality rates for major abdominal surgery have been 10%, 30%, and 76%–82% for Child-Pugh classifications A, B, and C, respectively [11]. Whereas, according to the MELD score, the 30-day mortalities after surgery were reported to be 6% for MELD < 8 and 50% for MELD > 20 [12]. However, until now, to our best knowledge, only a few studies have been published on the outcomes of PD in patients with LC. A retrospective multicentre study reported that PH and a serum aspartate aminotransferase (AST) of <50 IU/L were significant independent risk factors for hepatic decompensation, and an AST of < 50 IU/L and an AST-to-platelet-ratio index (APRI) ≥ 1.0 for a patient with a Child-Pugh B classification may be indications that PD can be performed [13]. At the first visit, our patient’s AST value, APRI value, and Child-Pugh score were 57 IU/L, 1.6, and 5A, respectively. After 2 cycles of GS, her preoperative AST and APRI values had decreased to 22 IU/L and 0.5, respectively. Therefore, our patient had appropriate indications for undergoing a PD. Her postoperative Child-Pugh score has remained 5–6 (Class A), with no increase in the APRI (Table 1). The increase in the postoperative MELD score was considered to be due to her anorexia associated with S1 adjuvant chemotherapy.Table 1 Table of perioperative Child-Pugh and MELD scores and APRI score.
Table 1 Pre-treatment After 2 cycles of GS POM1 POM2 POM3 POM4 POM5 POM6
Child-Pugh score 5 5 5 5 5 6 6 5
MELD score 9 3 1 0 1 3 5 3
APRI 1.6 0.5 0.2 0.1 0.1 0.1 0.1 0.1
APRI: AST-to-platelet-ratio index.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy.
POM: Postoperative month.
Pancytopenia has a wide range of aetiologies, including malignancies (leukaemia, malignant lymphoma, myelodysplastic syndrome, myeloma), autoimmune conditions (aplastic anaemia, systemic lupus erythematosus [SLE]), hypersplenism due to LC, drugs, infections, and nutritional deficiencies, so the evaluation of a patient with pancytopenia requires a comprehensive approach [14]. Regarding the patient’s thrombocytopenia, the causes of thrombocytopenia often overlap with the causes of pancytopenia [15]. Because our patient did not have lymphadenopathy, SLE, recent extensive thrombosis, blasts or atypical cells at peripheral blood tests, abnormal findings in her bone marrow, abnormal lymph nodes on CT or PET-CT, signs of infection, recent changes in oral medication, or a history of gastrectomy, we excluded malignancies, autoimmune conditions, drug reactions, infections, and nutritional deficiencies from the differential diagnosis. CT showed dullness of the hepatic margins, splenomegaly, and presence of a collateral circulation; we concluded that her pancytopenia, including her thrombocytopenia, was caused by hypersplenism due to LC. Therefore, we did not think that a bone-marrow biopsy was a priority, compared with preoperative chemotherapy for pancreatic cancer.
Thrombocytopenia (platelet count < 150,000/μL) [16] can occur with the progression of LC. The production of thrombopoietin and sequestration of platelets in the spleen are the main mechanisms involved in the development of thrombocytopenia [17]. The treatments for thrombocytopenia due to LC have included platelet transfusions, medications, embolization of the SA, and splenectomy [18]. With our patient’s elevated CA19−9 level, the risk of recurrence of her pancreatic cancer was considered high, and we elected to add treatment for improving her pancytopenia in order to enable the safe administration of chemotherapy after her recurrence. Platelet transfusion was not performed because of her splenomegaly and because of the possibility of platelet sequestration followed by destruction. We did not administer a thrombopoietin receptor agonist such as eltrombopag, which is effective for thrombocytopenia, because the patient required treatment not only for her thrombocytopenia but also for her pancytopenia. Whether a partial splenic artery embolization (PSAE) or splenectomy should have been performed has been controversial. The complications of PSAE include peritonitis, splenic abscess, and portal vein thrombosis. Additionally, PSAE is an invasive procedure, with both significant cost and uncertain long-term benefits. These limitations make PSAE an unsuitable option for many patients with advanced LC [17]. Furthermore, Miyake et al. reported that platelet counts after splenectomy were significantly increased over platelet counts after PSAE [19]. On the other hand, although splenectomy is an effective option for improving pancytopenia, it is also invasive and occasionally results in massive loss of blood. Additionally, the main complications after splenectomy are overwhelming post-splenectomy infections (OPSIs), approximately 80% of which are pneumococcal, and portal vein thrombosis. The reported incidence of portal vein thrombosis after splenectomy for splenomegaly has ranged from 9% to 29% [17].
For our patient, we debated about performing a splenectomy. Ligation or embolization of the SA was also considered, but we considered the effect of those procedures to be limited, because the blood supply of the spleen was delivered via collateral circulation, including the left gastric artery, the stomach wall, and the middle colic artery [20,21]. Therefore, we decided to perform a splenectomy, which seemed to provide the most reliable effect of increasing the blood cell count for the chemotherapy after recurrence of pancreatic cancer [19]. After confirmation that there were no distant metastases after neoadjuvant chemotherapy, we finally performed a radical PD combined with splenectomy following the approval by a multidisciplinary team a few days before the surgery. The patient also received postoperative pneumococcal vaccine to prevent OPSI before she underwent chemotherapy. However, the vaccine should have been administered before surgery in this high-risk patient.
With regard to preoperative chemotherapy, Karl et al. reported the usefulness and low toxicity of chemotherapy administered by intra-arterial infusion, including isolated abdominal perfusion [22]. However, our patient also had an abdominal aortic aneurysm with type 2 endoleak despite her previous EVAR, so catheterization was considered to be difficult. Additionally, her pretreatment CA19−9 level was very high (CA19−9 3909 U/mL), suggesting the possibility of micrometastases. Therefore, we elected to perform dose-reduced systemic chemotherapy for the early treatment and suppression of micrometastatic disease.
To our best knowledge, when limited to cases of PD synchronous with splenectomy for PC with pancytopenia due to LC, a total of 2 cases have been reported, including our case [23]. As in our patient, who lost a large volume of blood, Futagawa et al. reported a large blood loss (1700 mL). In patients with LC, bleeding occurs readily because of PH and decreased coagulability, and there is concern that hepatic function may deteriorate because of blood transfusions. Therefore, the control of intraoperative bleeding by reliable haemostasis is important. Furthermore, in patients with PH in whom collateral circulation develops, attention must be paid to the extent of lymph node dissection. Dissection of the hepatoduodenal ligament interrupts the collateral circulation, which can lead to refractory ascites and hepatic decompensation. Group 1 and 2 lymph node dissections were performed for our patient, who did not develop hepatic decompensation. However, careful planning that takes into consideration a patient’s overall condition and degree of liver damage is needed before surgery for these patients.
When PD is performed for a patient with LC, prevention of hepatic decompensation, which is directly is associated with mortality, is the most important consideration. Optimal perioperative management may decrease morbidity and mortality following surgery. Perioperative management for patients with LC includes nutritional management, control of refractory ascites and glucose levels, and correction of coagulopathy. These measures can help in preventing infection, hepatic encephalopathy and hepatic decompensation [24]. In our case, enteral nutrition therapy was started immediately after surgery for nutritional management and the prevention of postoperative infections [25]. In addition, since patients with LC who undergo PD, which is a highly invasive procedure, have increased risk of postoperative morbidity and mortality, careful monitoring and follow up are essential.
4 Conclusions
Strict indications for PD, control of intraoperative bleeding, and optimal perioperative management are important for preventing hepatic decompensation. Even for patients with PC and pancytopenia due to LC, PD combined with splenectomy is an effective treatment option.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Funding
This study did not receive any specific grants from funding agencies in the public, commercial, and not-for-profit sectors.
Ethical approval
This study was exempt from ethical approval at our institution.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
HT (certified by the Japanese Society of Gastroenterological Surgery) performed the surgery on this patient. IH, HT, KM, and TH managed the postoperative course of this patient. HT and HI wrote the manuscript. All authors have read and approved the final manuscript.
Registration of research studies
Not Applicable.
Guarantor
Hideharu Tanaka (Corresponding author and guarantor).
Provenance and peer review
Not commissioned, externally peer-reviewed.
Availability of data and materials
Not applicable.
Acknowledgements
The authors wish to thank JAM Post for the editing of a draft of this manuscript. | 100 MILLIGRAM/SQ. METER ON DAYS 1?14 OF A 21?DAY CYCLE | DrugDosageText | CC BY | 33689973 | 19,088,732 | 2021-04 |
What was the outcome of reaction 'Neutropenia'? | Pancreaticoduodenectomy combined with splenectomy for a patient with pancreatic cancer and pancytopenia due to liver cirrhosis: Case report.
The incidence of patients with liver cirrhosis (LC) is increasing. Patients with LC are known to have a greater risk of postoperative morbidity and mortality than patients without LC. A treatment option such as pancreaticoduodenectomy (PD) has not been validated to be safe for these patients, especially those with pancytopenia due to portal hypertension (PH). Providing an effective treatment option for these patients is essential.
METHODS
Herein, we describe a patient with pancreatic cancer with pancytopenia due to LC that was successfully treated with PD combined with splenectomy. The patient was a 70-year-old woman who was referred to our hospital for evaluation of a mass in the pancreatic head after she developed obstructive jaundice. She was diagnosed with T2N0M0, Stage IB pancreatic cancer and pancytopenia due to PH associated with LC. She received 2 cycles of adjuvant gemcitabine/S-1 chemotherapy and underwent radical subtotal stomach-preserving pancreaticoduodenectomy with splenectomy to improve her pancytopenia. Histopathological examination of the resected specimen revealed an R0 resection showing an Evans grade IIa histological response. Her pancytopenia improved rapidly after surgery.
Strict indications for PD, haemostatic control of intraoperative bleeding, and optimal perioperative management were important for preventing hepatic decompensation in this patient. Splenectomy is effective for thrombocytopenia due to LC; however, attention to postoperative complications such as overwhelming post-splenectomy infection and portal vein thrombosis is required.
CONCLUSIONS
For patients with pancreatic cancer with pancytopenia due to LC, PD combined with splenectomy plus optimal perioperative management is effective.
1 Introduction
Patients with liver cirrhosis (LC) have been recognized to have a greater risk of postoperative morbidity and mortality than patients without LC [1,2]. The safety of pancreaticoduodenectomy (PD) for patients with chronic hepatic dysfunction due to LC has not been validated. The risk of pancreaticoduodenectomy (PD) for patients increases with the progression of LC, because of the development of pancytopenia due to portal hypertension (PH) and secondary hypersplenism.
Perioperative chemotherapy has played an increasingly important role in the treatment of patients with pancreatic cancer (PC). Therefore, it is important to provide appropriate treatment options, including chemotherapy, for a patient with PC and pancytopenia due to LC. Herein we describe a patient with PC with pancytopenia due to LC who was successfully treated by PD combined with splenectomy, which enabled the safe postoperative administration of chemotherapy. We report this case in accordance with the 2020 SCARE criteria [3].
2 Case report
A 70-year-old woman with obstructive jaundice underwent percutaneous transhepatic biliary drainage instead of endoscopic biliary drainage because of her duodenal stenosis. She was then referred to our hospital for evaluation of a pancreatic head lesion that had been identified on an abdominal computed tomography (CT) scan performed when her jaundice had been discovered. She had a past history of endovascular aneurysmal repair (EVAR) for an abdominal aortic aneurysm one year previously and an appendectomy followed by surgery for an ileus when she was 10 years of age. Her family history was negative for pancreatic cancer and genetic disorders. She was 151 cm tall and weighed 60 kg. Her body-mass index was 26.3. The results of her physical examination were unremarkable.
Laboratory analysis revealed pancytopenia (white blood cell count 2710/μL, red blood cell count 366 × 104/μL, haemoglobin 10.9 g/dL, platelet count 89 × 103/μL) and CA19−9 3909 U/mL). She was negative for hepatitis B surface antigen and anti-hepatitis C virus antibody. Her Child-Pugh score and Model for End-stage Liver Disease (MELD) score were Grade 5A and 9, respectively [[4], [5], [6]]. Enhanced multidetector-row computed tomography (CT) revealed a 25-mm hypovascular tumour in the pancreatic groove, which had invaded the duodenum and lower bile duct (Fig. 1a). No other metastases involving distant organs were seen. Dullness of the hepatic margins was observed, and the spleen appeared enlarged, with a maximum diameter of 15 cm, suggesting portal hypertension (PH) (Fig. 1b). Endoscopic ultrasound-guided fine needle aspiration was performed. The cytopathological findings revealed pancreatic adenocarcinoma. Based on the 8th edition of the UICC criteria, the findings were diagnosed to be T2N0M0, Stage IB pancreatic carcinoma.Fig. 1 Pretreatment coronal enhanced computed tomography images.
a) Hypovascular 25-mm tumour (white arrow) in the pancreatic groove invading the duodenum and lower bile duct.
b) Splenomegaly with a maximum splenic diameter of 15 cm, which suggests portal hypertension.
Fig. 1
In accordance with the findings of the phase 2/3 Prep-02/JSAP05 trial [7], the patient underwent neoadjuvant gemcitabine/S-1 (GS) chemotherapy (gemcitabine [800 mg/m2] on days 1, 8 and S-1 [100 mg/m2] on days 1–14 of a 21-day cycle) repeated every 3 weeks for 2 cycles. Because of the patient’s pretreatment pancytopenia (neutrophil count 2250/μL), gemcitabine and S-1 were reduced by 200 mg/m2/day to 800 mg/m2/day, and 20 mg/m2/day to 100 mg/m2/day, respectively. Even after the dose reduction, neutropenia (neutrophil count 1340/μL) was observed during 1 cycle of GS, and chemotherapy was withheld until the neutropenia was resolved. Although the patient’s serum CA 19−9 level decreased after 2 cycles of GS chemotherapy, it remained elevated (CA 19−9 1064 U/mL). After 2 cycles, the primary tumour had slightly decreased to a diameter of 24 mm. Since the level of her CA19−9 tumour marker remained elevated, her risk of postoperative recurrence after PD was high. However, if the tumour recurred, the administration of intensive chemotherapy such as FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel regimens would be difficult because of the patient’s pancytopenia. Therefore, we elected to perform a splenectomy in addition to the PD to improve her pancytopenia.
Splenectomy for splenomegaly with PH occasionally results in loss of a large amount of blood, which requires a large transfusion. The transfusion leads to oedema of the intestinal wall, which can increase the difficulty of performing a PD. Therefore, we decided to perform the PD followed by splenectomy.
The intraoperative findings revealed a liver with a granular surface and dullness of the liver’s edge (Fig. 2). We performed extensive detachment of the adhesions due to the patient’s previous appendectomy and subsequent surgery for an ileus, and found that detaching the hepatoduodenal ligament was difficult because of her repeated preoperative episodes of cholangitis. Since the collateral hepatic circulation that had developed bled easily, haemostasis was performed safely by ligation. After the PD, we began the splenectomy. We first detached and ligated the splenic artery (SA) at the upper edge of the pancreatic body to shrink the spleen and reduce the amount of blood loss. The splenic vein (SV) was also ligated, but the splenic hilum bled heavily because of tension on the SV. Haemostasis was performed by ligation while elevating the splenic hilum from the dorsal side. Finally, we performed a radical subtotal stomach-preserving PD with splenectomy, and lymph node dissections of groups 1 and 2 that included the hepatoduodenal ligament caudal to the hilar plate. The operative time was 12 h and 7 min, and the volume of blood loss was 1990 mL.Fig. 2 Intraoperative image.
Intraoperative findings show the dullness of the liver’s edge and its granular surface.
Fig. 2
The excised specimens showed a solid tumour in the pancreatic head which had invaded the duodenum and bile duct (Fig. 3a), and splenomegaly (Fig. 3b). The histopathological diagnosis was invasive ductal carcinoma with severe venous invasion and moderate nerve infiltration, ypT2N0M0, ypStage IB pancreatic cancer, as based on the 8th Edition of the UICC criteria and grade IIa as based on the Evans classification [8] (Fig. 4).Fig. 3 Macroscopic views of the resected specimens.
a) Macroscopic image of the resected specimen shows a mass in the pancreatic head, which has invaded the duodenum and bile duct.
b) The resected spleen is enlarged.
Fig. 3
Fig. 4 Photomicrograph (haematoxylin-and-eosin stain).
Malignant cells (arrows) have invaded the bile ducts (arrowheads).
Fig. 4
The patient’s pancytopenia improved rapidly after surgery. The platelet count increased rapidly after splenectomy, peaking at 681,000/μL on postoperative day (POD) 16, and then decreasing to the normal range (Fig. 5). However, the patient developed atelectasis and splenic vein thrombosis, which were considered Grade II complications in accordance with the Clavien-Dindo classification. The patient received high-flow nasal oxygen therapy and noninvasive positive-pressure ventilation, including bilevel positive airway pressure, and was prescribed an anticoagulant agent for the thrombosis. The patient was moved out of the intensive care unit on POD 5, and discharged on POD 30. After having received adjuvant chemotherapy with S-1 for 2 months due to the anorexia, the patient underwent blood tests and CT scans every 3 months. Nine months after her PD, a liver metastasis was detected, for which she received chemotherapy. She has remained alive for 13 months after her PD.Fig. 5 Graph of platelet and white blood cell counts over the patient’s hospital course.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy
Adjuvant S-1: Adjuvant S-1 chemotherapy
Fig. 5
3 Discussion
The outcomes of surgery in patients with LC have been reported to vary, based not only on the degree of damage to the liver but also the invasiveness of the surgery [9]. The reported mortality of major abdominal surgery for patients with LC is 35% [10]. The Child-Pugh classification and the MELD score have been useful for estimating the risk of surgical mortality. According to the Child-Pugh classification, the mortality rates for major abdominal surgery have been 10%, 30%, and 76%–82% for Child-Pugh classifications A, B, and C, respectively [11]. Whereas, according to the MELD score, the 30-day mortalities after surgery were reported to be 6% for MELD < 8 and 50% for MELD > 20 [12]. However, until now, to our best knowledge, only a few studies have been published on the outcomes of PD in patients with LC. A retrospective multicentre study reported that PH and a serum aspartate aminotransferase (AST) of <50 IU/L were significant independent risk factors for hepatic decompensation, and an AST of < 50 IU/L and an AST-to-platelet-ratio index (APRI) ≥ 1.0 for a patient with a Child-Pugh B classification may be indications that PD can be performed [13]. At the first visit, our patient’s AST value, APRI value, and Child-Pugh score were 57 IU/L, 1.6, and 5A, respectively. After 2 cycles of GS, her preoperative AST and APRI values had decreased to 22 IU/L and 0.5, respectively. Therefore, our patient had appropriate indications for undergoing a PD. Her postoperative Child-Pugh score has remained 5–6 (Class A), with no increase in the APRI (Table 1). The increase in the postoperative MELD score was considered to be due to her anorexia associated with S1 adjuvant chemotherapy.Table 1 Table of perioperative Child-Pugh and MELD scores and APRI score.
Table 1 Pre-treatment After 2 cycles of GS POM1 POM2 POM3 POM4 POM5 POM6
Child-Pugh score 5 5 5 5 5 6 6 5
MELD score 9 3 1 0 1 3 5 3
APRI 1.6 0.5 0.2 0.1 0.1 0.1 0.1 0.1
APRI: AST-to-platelet-ratio index.
GS: Neoadjuvant gemcitabine/S-1 chemotherapy.
POM: Postoperative month.
Pancytopenia has a wide range of aetiologies, including malignancies (leukaemia, malignant lymphoma, myelodysplastic syndrome, myeloma), autoimmune conditions (aplastic anaemia, systemic lupus erythematosus [SLE]), hypersplenism due to LC, drugs, infections, and nutritional deficiencies, so the evaluation of a patient with pancytopenia requires a comprehensive approach [14]. Regarding the patient’s thrombocytopenia, the causes of thrombocytopenia often overlap with the causes of pancytopenia [15]. Because our patient did not have lymphadenopathy, SLE, recent extensive thrombosis, blasts or atypical cells at peripheral blood tests, abnormal findings in her bone marrow, abnormal lymph nodes on CT or PET-CT, signs of infection, recent changes in oral medication, or a history of gastrectomy, we excluded malignancies, autoimmune conditions, drug reactions, infections, and nutritional deficiencies from the differential diagnosis. CT showed dullness of the hepatic margins, splenomegaly, and presence of a collateral circulation; we concluded that her pancytopenia, including her thrombocytopenia, was caused by hypersplenism due to LC. Therefore, we did not think that a bone-marrow biopsy was a priority, compared with preoperative chemotherapy for pancreatic cancer.
Thrombocytopenia (platelet count < 150,000/μL) [16] can occur with the progression of LC. The production of thrombopoietin and sequestration of platelets in the spleen are the main mechanisms involved in the development of thrombocytopenia [17]. The treatments for thrombocytopenia due to LC have included platelet transfusions, medications, embolization of the SA, and splenectomy [18]. With our patient’s elevated CA19−9 level, the risk of recurrence of her pancreatic cancer was considered high, and we elected to add treatment for improving her pancytopenia in order to enable the safe administration of chemotherapy after her recurrence. Platelet transfusion was not performed because of her splenomegaly and because of the possibility of platelet sequestration followed by destruction. We did not administer a thrombopoietin receptor agonist such as eltrombopag, which is effective for thrombocytopenia, because the patient required treatment not only for her thrombocytopenia but also for her pancytopenia. Whether a partial splenic artery embolization (PSAE) or splenectomy should have been performed has been controversial. The complications of PSAE include peritonitis, splenic abscess, and portal vein thrombosis. Additionally, PSAE is an invasive procedure, with both significant cost and uncertain long-term benefits. These limitations make PSAE an unsuitable option for many patients with advanced LC [17]. Furthermore, Miyake et al. reported that platelet counts after splenectomy were significantly increased over platelet counts after PSAE [19]. On the other hand, although splenectomy is an effective option for improving pancytopenia, it is also invasive and occasionally results in massive loss of blood. Additionally, the main complications after splenectomy are overwhelming post-splenectomy infections (OPSIs), approximately 80% of which are pneumococcal, and portal vein thrombosis. The reported incidence of portal vein thrombosis after splenectomy for splenomegaly has ranged from 9% to 29% [17].
For our patient, we debated about performing a splenectomy. Ligation or embolization of the SA was also considered, but we considered the effect of those procedures to be limited, because the blood supply of the spleen was delivered via collateral circulation, including the left gastric artery, the stomach wall, and the middle colic artery [20,21]. Therefore, we decided to perform a splenectomy, which seemed to provide the most reliable effect of increasing the blood cell count for the chemotherapy after recurrence of pancreatic cancer [19]. After confirmation that there were no distant metastases after neoadjuvant chemotherapy, we finally performed a radical PD combined with splenectomy following the approval by a multidisciplinary team a few days before the surgery. The patient also received postoperative pneumococcal vaccine to prevent OPSI before she underwent chemotherapy. However, the vaccine should have been administered before surgery in this high-risk patient.
With regard to preoperative chemotherapy, Karl et al. reported the usefulness and low toxicity of chemotherapy administered by intra-arterial infusion, including isolated abdominal perfusion [22]. However, our patient also had an abdominal aortic aneurysm with type 2 endoleak despite her previous EVAR, so catheterization was considered to be difficult. Additionally, her pretreatment CA19−9 level was very high (CA19−9 3909 U/mL), suggesting the possibility of micrometastases. Therefore, we elected to perform dose-reduced systemic chemotherapy for the early treatment and suppression of micrometastatic disease.
To our best knowledge, when limited to cases of PD synchronous with splenectomy for PC with pancytopenia due to LC, a total of 2 cases have been reported, including our case [23]. As in our patient, who lost a large volume of blood, Futagawa et al. reported a large blood loss (1700 mL). In patients with LC, bleeding occurs readily because of PH and decreased coagulability, and there is concern that hepatic function may deteriorate because of blood transfusions. Therefore, the control of intraoperative bleeding by reliable haemostasis is important. Furthermore, in patients with PH in whom collateral circulation develops, attention must be paid to the extent of lymph node dissection. Dissection of the hepatoduodenal ligament interrupts the collateral circulation, which can lead to refractory ascites and hepatic decompensation. Group 1 and 2 lymph node dissections were performed for our patient, who did not develop hepatic decompensation. However, careful planning that takes into consideration a patient’s overall condition and degree of liver damage is needed before surgery for these patients.
When PD is performed for a patient with LC, prevention of hepatic decompensation, which is directly is associated with mortality, is the most important consideration. Optimal perioperative management may decrease morbidity and mortality following surgery. Perioperative management for patients with LC includes nutritional management, control of refractory ascites and glucose levels, and correction of coagulopathy. These measures can help in preventing infection, hepatic encephalopathy and hepatic decompensation [24]. In our case, enteral nutrition therapy was started immediately after surgery for nutritional management and the prevention of postoperative infections [25]. In addition, since patients with LC who undergo PD, which is a highly invasive procedure, have increased risk of postoperative morbidity and mortality, careful monitoring and follow up are essential.
4 Conclusions
Strict indications for PD, control of intraoperative bleeding, and optimal perioperative management are important for preventing hepatic decompensation. Even for patients with PC and pancytopenia due to LC, PD combined with splenectomy is an effective treatment option.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Funding
This study did not receive any specific grants from funding agencies in the public, commercial, and not-for-profit sectors.
Ethical approval
This study was exempt from ethical approval at our institution.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
HT (certified by the Japanese Society of Gastroenterological Surgery) performed the surgery on this patient. IH, HT, KM, and TH managed the postoperative course of this patient. HT and HI wrote the manuscript. All authors have read and approved the final manuscript.
Registration of research studies
Not Applicable.
Guarantor
Hideharu Tanaka (Corresponding author and guarantor).
Provenance and peer review
Not commissioned, externally peer-reviewed.
Availability of data and materials
Not applicable.
Acknowledgements
The authors wish to thank JAM Post for the editing of a draft of this manuscript. | Recovered | ReactionOutcome | CC BY | 33689973 | 19,088,732 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute myocardial infarction'. | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | ATROPINE, AXITINIB, CARVEDILOL, DOPAMINE HYDROCHLORIDE, EPINEPHRINE, HYDROCORTISONE, LEVOTHYROXINE, LIOTHYRONINE, MAGNESIUM, NOREPINEPHRINE, PEMBROLIZUMAB, PHENYLEPHRINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33690260 | 19,262,192 | 2021-03-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac arrest'. | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | ATROPINE, AXITINIB, CARVEDILOL, DOPAMINE HYDROCHLORIDE, EPINEPHRINE, HYDROCORTISONE, LEVOTHYROXINE, LIOTHYRONINE, MAGNESIUM, NOREPINEPHRINE, PEMBROLIZUMAB, PHENYLEPHRINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33690260 | 19,262,192 | 2021-03-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiogenic shock'. | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | ATROPINE, AXITINIB, CARVEDILOL, DOPAMINE HYDROCHLORIDE, EPINEPHRINE, HYDROCORTISONE, LEVOTHYROXINE, LIOTHYRONINE, MAGNESIUM, NOREPINEPHRINE, PEMBROLIZUMAB, PHENYLEPHRINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33690260 | 19,262,192 | 2021-03-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'General physical health deterioration'. | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | AXITINIB, CARVEDILOL, HYDROCORTISONE BUTYRATE, LEVOTHYROXINE, LIOTHYRONINE SODIUM, PEMBROLIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33690260 | 19,084,047 | 2021-03-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myxoedema coma'. | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | ATROPINE, AXITINIB, CARVEDILOL, DOPAMINE HYDROCHLORIDE, EPINEPHRINE, HYDROCORTISONE, LEVOTHYROXINE, LIOTHYRONINE, MAGNESIUM, NOREPINEPHRINE, PEMBROLIZUMAB, PHENYLEPHRINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33690260 | 19,262,192 | 2021-03-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pericardial effusion'. | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | ATROPINE, AXITINIB, CARVEDILOL, DOPAMINE HYDROCHLORIDE, EPINEPHRINE, HYDROCORTISONE, LEVOTHYROXINE, LIOTHYRONINE, MAGNESIUM, NOREPINEPHRINE, PEMBROLIZUMAB, PHENYLEPHRINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33690260 | 19,262,192 | 2021-03-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Secondary adrenocortical insufficiency'. | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | ATROPINE, AXITINIB, CARVEDILOL, DOPAMINE HYDROCHLORIDE, EPINEPHRINE, HYDROCORTISONE, LEVOTHYROXINE, LIOTHYRONINE, MAGNESIUM, NOREPINEPHRINE, PEMBROLIZUMAB, PHENYLEPHRINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33690260 | 19,262,192 | 2021-03-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sinus bradycardia'. | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | ATROPINE, AXITINIB, CARVEDILOL, DOPAMINE HYDROCHLORIDE, EPINEPHRINE, HYDROCORTISONE, LEVOTHYROXINE, LIOTHYRONINE, MAGNESIUM, NOREPINEPHRINE, PEMBROLIZUMAB, PHENYLEPHRINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33690260 | 19,262,192 | 2021-03-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Torsade de pointes'. | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | ATROPINE, AXITINIB, CARVEDILOL, DOPAMINE HYDROCHLORIDE, EPINEPHRINE, HYDROCORTISONE, LEVOTHYROXINE, LIOTHYRONINE, MAGNESIUM, NOREPINEPHRINE, PEMBROLIZUMAB, PHENYLEPHRINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33690260 | 19,262,192 | 2021-03-10 |
What was the administration route of drug 'ATROPINE'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33690260 | 19,200,757 | 2021-03-10 |
What was the administration route of drug 'AXITINIB'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33690260 | 19,084,047 | 2021-03-10 |
What was the administration route of drug 'CARVEDILOL'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33690260 | 19,200,757 | 2021-03-10 |
What was the administration route of drug 'DOPAMINE HYDROCHLORIDE'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Intravenous drip | DrugAdministrationRoute | CC BY-NC-ND | 33690260 | 19,069,405 | 2021-03-10 |
What was the administration route of drug 'EPINEPHRINE'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33690260 | 19,200,757 | 2021-03-10 |
What was the administration route of drug 'HYDROCORTISONE BUTYRATE'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33690260 | 19,084,047 | 2021-03-10 |
What was the administration route of drug 'HYDROCORTISONE SODIUM SUCCINATE'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33690260 | 19,069,405 | 2021-03-10 |
What was the administration route of drug 'HYDROCORTISONE'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33690260 | 19,200,757 | 2021-03-10 |
What was the administration route of drug 'LIOTHYRONINE SODIUM'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33690260 | 19,084,047 | 2021-03-10 |
What was the administration route of drug 'LIOTHYRONINE'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33690260 | 19,200,757 | 2021-03-10 |
What was the administration route of drug 'MAGNESIUM'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33690260 | 19,200,757 | 2021-03-10 |
What was the administration route of drug 'PEMBROLIZUMAB'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33690260 | 19,084,047 | 2021-03-10 |
What was the dosage of drug 'HYDROCORTISONE SODIUM SUCCINATE'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | 100 MG | DrugDosageText | CC BY-NC-ND | 33690260 | 19,069,405 | 2021-03-10 |
What was the dosage of drug 'HYDROCORTISONE'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | 100 MILLIGRAM | DrugDosageText | CC BY-NC-ND | 33690260 | 19,200,757 | 2021-03-10 |
What was the dosage of drug 'MAGNESIUM'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | 2 GRAM | DrugDosageText | CC BY-NC-ND | 33690260 | 19,200,757 | 2021-03-10 |
What was the dosage of drug 'NOREPINEPHRINE BITARTRATE'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | 200 UG (200 MCG/MIN) | DrugDosageText | CC BY-NC-ND | 33690260 | 19,069,405 | 2021-03-10 |
What was the outcome of reaction 'Drug ineffective'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Fatal | ReactionOutcome | CC BY-NC-ND | 33690260 | 19,069,405 | 2021-03-10 |
What was the outcome of reaction 'General physical health deterioration'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Fatal | ReactionOutcome | CC BY-NC-ND | 33690260 | 19,084,047 | 2021-03-10 |
What was the outcome of reaction 'Treatment failure'? | An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.
BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.
Background
Myxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.
Decreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].
Thyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].
To the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.
Case Report
A 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.
His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.
His past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.
Upon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.
Prior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.
Left and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.
A transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.
Arterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.
A diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.
Despite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.
Discussion
A review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.
Although the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].
Our patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.
There are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.
The second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].
In addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.
Our patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.
Our patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.
When myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].
Conclusions
Our case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.
It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.
Figure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.
Figure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).
Figure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).
Table 1. Laboratory data.
Laboratory data Value Normal range
Sodium 118 mmol/L (135–146) mmol/L
Potassium 3.2 mmol/L (3.5–5.3) mmol/L
Chloride 85 mmol/L (98–107) mmol/L
HCO3 23 mmol/L (21–32) mmol/L
Glucose 568 mg/dL (65–99) mg/dL
BUN 13 mg/dL (7–23) mg/dL
Creatinine 1.4 mg/dL (0.5–1.2) mg/dL
AST 329 IU/L (5–40) IU/L
ALT 160 IU/L (7–56) IU/L
WBC 11.7×109/L (4.0–10.5) K/UL
Hemoglobin 13 g/dL (13.0–18.0) G/dL
TSH 60.6 mIU/L (0.465–4.680) mIU/ML
Free T4 0.3 ng/dL (0.8–2.2) ng/dL
Cortisol 2.0 mcg/dl (1.7–14.1) mcg/dl
Troponin I 0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours <0.01 ng/ml
Conflicts of Interest
None. | Fatal | ReactionOutcome | CC BY-NC-ND | 33690260 | 19,084,047 | 2021-03-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Case Report: Bupropion Reduces the [123I]FP-CIT Binding to Striatal Dopamine Transporter.
The diagnosis of parkinsonian syndromes in patients with severe depression may be challenging due to overlapping clinical phenomena, especially regarding psychomotor and affective symptoms. [123I]FP-CIT-SPECT is a useful method to detect degenerative parkinsonian disorders. However, some drugs may influence the tracer binding and thus alter the result. We present a case of 56-year-old female inpatient with difficult-to-treat late-onset depression. Since the current major depressive episode (MDE) was accompanied by psychotic features including delusions and hallucinations as well as hypokinesia, stooped posture and hypomimia, underlying degenerative parkinsonism was suspected. The pathologic [123I]FP-CIT-SPECT scan under ongoing antidepressant therapy with bupropion 300 mg/die (serum level of bupropion 43 ng/ml and hydroxybupropion 2,332 ng/ml) showed reduced [123I]FP-CIT binding throughout the striatum. The scan normalized upon a wash-out phase of four half-time periods (serum level of bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with the dopamine transporter. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to dopamine transporter imaging.
Introduction
The diagnosis of parkinsonian syndromes in patients suffering from severe depression can be challenging. On one hand, these patients may exhibit hypomimia-like facial expression, parkinsonian-like posture or develop psychotic features (1). On the other hand, depression as the most common non-motor symptom in Parkinson's disease (PD) precedes the motor symptoms for ~10 years (2). In doubtful cases, [123I]FP-CIT-SPECT is a useful tool to detect decrease in striatal binding to dopamine transporters (DAT) (3) due to loss of nigrostriatal terminals (4). However, commonly prescribed psychopharmacotherapeutics that bind to DAT may change the binding properties of the tracer (5) and hence, alter the results (6). Although several drugs have been identified, occasionally patients and physicians are not aware that these drugs ought to be paused prior to [123I]FP-CIT-SPECT imaging. This results either in prolonging the diagnostic procedures or, if not considered by specialists, even in imprecise diagnosis. Here we report on a prominent effect of short-term bupropion therapy on [123I]FP-CIT-SPECT imaging.
Case Presentation
The 56-year-old female inpatient (weight: 70 kg, height: 160 cm) had almost a 1-year history of a difficult-to-treat depression (7) with late onset (8). In the course of the current severe major depressive episode (MDE) with psychotic symptoms (International Classification of Diseases, 10th revision, ICD-10 (9): F32.3) that represented her first MDE so far, the patient was anhedonic and exhibited indecisiveness, feelings of hopelessness and worthlessness as well as excessive guilt and diminished ability to concentrate. In the course of her subjective cognitive decline, the patient exhibited a total score of 28/30 at the Mini-Mental State Examination (MMSE) (10) and of 15/18 at the DemTect (11) representing values within the normal range. Furthermore, she suffered from psychomotor slowing, loss of interest and pleasure affecting her hobbies and nearly all activities including the necessary daily routine, as well as delusions and hallucinations. She negated suicidal ideation and there was no suicidal history. The patient showed a total score of 46 at the Montgomery-Åsberg Depression Rating Scale (MADRS) (12) and 6 at the Clinical Global Impressions Scale (CGI-S) (13). In terms of psychiatric and somatic comorbidities, the patient suffered from nicotine dependence (ICD-10: F17.2) and psoriasis vulgaris (ICD-10: L40.0).
The antidepressant combination treatment with mirtazapine 45 mg and venlafaxine 375 mg was expanded with vortioxetine 10 mg/die, but failed to improve the symptoms. Neither augmentation with second-generation antipsychotics (aripiprazole 20 mg/die) (14) and S-ketamine (15) that was administered 2–3 times/week intravenously (up to 50 mg per infusion), nor a series of 11 electroconvulsive therapies (ECT) with subsequent regular maintenance ECTs, all with bilateral stimulation up to 100%, improved the severe depressive symptoms (16).
Due to massive anhedonia, progressive hypomimia, general slowness of movements, delusions and hallucinations, a suspicion of degenerative parkinsonism was raised. Since there were no postural instability and no history of falls, dementia with Lewy bodies (DLB) was considered as a differential diagnosis. While the cranial magnetic resonance imaging was unremarkable, [123I]FP-CIT-SPECT was initiated. Four days prior to the [123I]FP-CIT-SPECT examination the antidepressant treatment was adapted adding bupropion 150 mg/die that was increased to 300 mg/die on the day of [123I]FP-CIT-SPECT. An intravenous bolus injection of ~185 MBq [123I]FP-CIT according to GMP criteria was applied ~1 h after the medication intake and ~3 h before the acquisition of the scans. A three-headed Gamma camera (IRIX 465, Philips Medical System) system was used for SPECT Imaging (3° steps/360°, 60 s per step, 40 frames, pixel size of 3,50 mm, pixel matrix of 128 × 128, LEHR-PAR collimator). OSEM reconstruction (5 subsets, 16 iterations), post-filtering with 3 D Gauss filter (FWHM 7 cm) and Chang's attenuation correction (17) with an attenuation coefficient of 0.15 for all images were performed. [123I]FP-CIT-SPECT was reported pathologic with reductions of striatal DAT binding bilaterally (arrow in Figure 1A) and low contrast between striatal and cortical binding (arrowheads in Figure 1A). The specific binding ratio was calculated using occipital region as a reference (18), and the standard deviations from the reference value mean (Z-score) were calculated using BRASS HERMES software containing age-corrected control population: left caudate nucleus 1.77 (Z-Score −4.2), right caudate 1.81 (Z-Score −3.91), left putamen 1.68 (Z-Score −3.65), and right putamen 1.54 (Z-Score −4.08).
Figure 1 Representative [123I]FP-CIT-SPECT images of the patient. Note inhomogeneous and reduced dopamine transporter binding of the radiopharmaceutical in putamen bilaterally (arrow in A) and low contrast between striatal and cortical binding during short-term bupropion therapy (arrowheads in A), which normalized after a wash-out phase of four half-life periods (arrow and arrowheads in B). Bupropion reduced the binding of [123I]FP-CIT up to 45% (i.e., in right putamen).
Subsequently, consultant neurologist was involved revealing general slowness of movements without true bradykinesia with bilateral reduction of arm pendular movement upon walking. Rigidity was not detected, but active resistance. Importantly, the ongoing therapy with bupropion was noted, whereby the serum blood levels of bupropion (43 ng/ml) and the active metabolite hydroxybupropion (2,332 ng/ml) measured on the day of the neurologic examination were within the therapeutic range. Once the repetition of [123I]FP-CIT SPECT after a wash-out phase was suggested, bupropion was discontinued for 8 days (half-life period 20–37 h). At the day of [123I]FP-CIT-SPECT rescan, the serum blood level for bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml. [123I]FP-CIT SPECT was reported normal (Figure 1B) using the same analysis, with overall normalization of specific binding ratios and Z-scores: left caudate nucleus 3.18 (Z-score −0.2), right caudate nucleus 3.28 (Z-score −0.63), left putamen 3.08 (Z-score −0.51) and right putamen 2.94 (Z-score −0.05).
In the course of the comprehensive differential diagnostics, laboratory tests including blood, urine and cerebrospinal fluid, electroencephalography, and [18F]-FDG PET/CT were performed revealing largely unremarkable results. After degenerative parkinsonism, dementia, autoimmune encephalitis, and other degenerative and inflammatory processes could be excluded, further therapeutic optimization was undertaken. While the antidepressant treatment with venlafaxine and vortioxetine was discontinued, tranylcypromine was initiated after the necessary wash-out phase. While staying on a low-tyramine diet, tranylcypromine was well-tolerated by the patient who partially responded to this treatment adaptation. Subsequently, tranylcypromine was slowly increased up to 50 mg/die. Moreover, the patient received clozapine as additional augmentation treatment that was gradually optimized up to 100 mg/die. Under a treatment regimen including tranylcypromine 50 mg, mirtazapine 30 mg, clozapine 100 mg, aripiprazole 10 mg, and clonazepam 2 mg/die that was accompanied by regular psychotherapeutic-, physiotherapeutic and ergotherapeutic support, a remarkable reduction of her depressive and psychotic symptoms was achieved. The adherent patient showed a total score of 28 at the MADRS and of four at the CGI-S and could be discharged from psychiatric inpatient care. Continuing the abovementioned psychopharmacotherapy she was subsequently treated as outpatient and received psychosocial support at home.
Discussion
The present case report could show effect of blood serum levels of bupropion and its active metabolite hydroxybupropion on [123I]FP-CIT binding to DAT. Hereby, therapeutic doses of bupropion reduced the binding of [123I]FP-CIT ~45–50% throughout the striatum, that was reversible after four half-life periods of bupropion. Since there was no further change in the ongoing therapy, in particular concerning venlafaxine and vortioxetine or mirtazapine, we attribute the observed effect to bupropion. Bupropion is a dose-dependent norepinephrine-dopamine reuptake inhibitor (19), with high occupancy at higher doses. Previous studies suggested changed DAT binding properties in depressed individuals. However, it is still a matter of debate, whether the primary mechanism is down-regulation (19) or up-regulation of DAT (20). Thus, concomitant therapy with bupropion may lead to a significant loss of [123I]FP-CIT binding and hence, might result in false positive diagnosis of degenerative parkinsonism. The [123I]FP-CIT binding pattern in our patient, however, appeared atypical for idiopathic PD and DLB (21), showing a reduced DAT binding throughout the striatum. Indeed, a recent paper noted similar observation, although some asymmetry in [123I]FP-CIT binding in a patient under bupropion therapy was reported (22). Thus, careful visual examination of DAT scan in a patient under dopaminergic medications, such as bupropion, may be critical (5). Taken together, our data suggest, that a discontinuation of bupropion of at least four half-life periods is necessary prior to [123I]FP-CIT scan. However, further prospective studies are needed to examine whether longer discontinuation is necessary, as suggested by some authors (22). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with DAT. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to DAT imaging. This might be of crucial importance especially in patients suffering from late onset depression that was recently related to elevated rates of motor and non-motor symptoms known from degenerative parkinsonian syndromes as well as to altered [123I]FP-CIT binding and, hence, to increased risk of PD and DLB (8).
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
IM and LB were responsible for clinical care and data analysis and drafted the manuscript. KP, DW, and SK supervised clinical care and critically revised the manuscript. TT-W critically revised the manuscript and performed and analyzed [123I]FP-CIT-SPECT scans. All authors contributed to the article and approved the submitted version.
Conflict of Interest
IM received grant from Takeda. LB received travel grants and consultant/speaker honoraria from AOP Orphan, Medizin Medien Austria, Vertretungsnetz, Schwabe Austria, Janssen, and Angelini. KP received honoraria from AOP Orphan Pharmaceuticals, Germania Pharmaceuticals, Lundbeck, and Janssen-Cilag. SK received grants/research support, consulting fees, and/or honoraria from Angelini, AOP Orphan Pharmaceuticals, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. DW received lecture fees/authorship honoraria from Angelini, Lundbeck, and Medizin Medien Austria. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | ARIPIPRAZOLE, BUPROPION, ESKETAMINE, IOFLUPANE I-123, MIRTAZAPINE, VENLAFAXINE HYDROCHLORIDE, VORTIOXETINE | DrugsGivenReaction | CC BY | 33692710 | 19,253,442 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug interaction'. | Case Report: Bupropion Reduces the [123I]FP-CIT Binding to Striatal Dopamine Transporter.
The diagnosis of parkinsonian syndromes in patients with severe depression may be challenging due to overlapping clinical phenomena, especially regarding psychomotor and affective symptoms. [123I]FP-CIT-SPECT is a useful method to detect degenerative parkinsonian disorders. However, some drugs may influence the tracer binding and thus alter the result. We present a case of 56-year-old female inpatient with difficult-to-treat late-onset depression. Since the current major depressive episode (MDE) was accompanied by psychotic features including delusions and hallucinations as well as hypokinesia, stooped posture and hypomimia, underlying degenerative parkinsonism was suspected. The pathologic [123I]FP-CIT-SPECT scan under ongoing antidepressant therapy with bupropion 300 mg/die (serum level of bupropion 43 ng/ml and hydroxybupropion 2,332 ng/ml) showed reduced [123I]FP-CIT binding throughout the striatum. The scan normalized upon a wash-out phase of four half-time periods (serum level of bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with the dopamine transporter. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to dopamine transporter imaging.
Introduction
The diagnosis of parkinsonian syndromes in patients suffering from severe depression can be challenging. On one hand, these patients may exhibit hypomimia-like facial expression, parkinsonian-like posture or develop psychotic features (1). On the other hand, depression as the most common non-motor symptom in Parkinson's disease (PD) precedes the motor symptoms for ~10 years (2). In doubtful cases, [123I]FP-CIT-SPECT is a useful tool to detect decrease in striatal binding to dopamine transporters (DAT) (3) due to loss of nigrostriatal terminals (4). However, commonly prescribed psychopharmacotherapeutics that bind to DAT may change the binding properties of the tracer (5) and hence, alter the results (6). Although several drugs have been identified, occasionally patients and physicians are not aware that these drugs ought to be paused prior to [123I]FP-CIT-SPECT imaging. This results either in prolonging the diagnostic procedures or, if not considered by specialists, even in imprecise diagnosis. Here we report on a prominent effect of short-term bupropion therapy on [123I]FP-CIT-SPECT imaging.
Case Presentation
The 56-year-old female inpatient (weight: 70 kg, height: 160 cm) had almost a 1-year history of a difficult-to-treat depression (7) with late onset (8). In the course of the current severe major depressive episode (MDE) with psychotic symptoms (International Classification of Diseases, 10th revision, ICD-10 (9): F32.3) that represented her first MDE so far, the patient was anhedonic and exhibited indecisiveness, feelings of hopelessness and worthlessness as well as excessive guilt and diminished ability to concentrate. In the course of her subjective cognitive decline, the patient exhibited a total score of 28/30 at the Mini-Mental State Examination (MMSE) (10) and of 15/18 at the DemTect (11) representing values within the normal range. Furthermore, she suffered from psychomotor slowing, loss of interest and pleasure affecting her hobbies and nearly all activities including the necessary daily routine, as well as delusions and hallucinations. She negated suicidal ideation and there was no suicidal history. The patient showed a total score of 46 at the Montgomery-Åsberg Depression Rating Scale (MADRS) (12) and 6 at the Clinical Global Impressions Scale (CGI-S) (13). In terms of psychiatric and somatic comorbidities, the patient suffered from nicotine dependence (ICD-10: F17.2) and psoriasis vulgaris (ICD-10: L40.0).
The antidepressant combination treatment with mirtazapine 45 mg and venlafaxine 375 mg was expanded with vortioxetine 10 mg/die, but failed to improve the symptoms. Neither augmentation with second-generation antipsychotics (aripiprazole 20 mg/die) (14) and S-ketamine (15) that was administered 2–3 times/week intravenously (up to 50 mg per infusion), nor a series of 11 electroconvulsive therapies (ECT) with subsequent regular maintenance ECTs, all with bilateral stimulation up to 100%, improved the severe depressive symptoms (16).
Due to massive anhedonia, progressive hypomimia, general slowness of movements, delusions and hallucinations, a suspicion of degenerative parkinsonism was raised. Since there were no postural instability and no history of falls, dementia with Lewy bodies (DLB) was considered as a differential diagnosis. While the cranial magnetic resonance imaging was unremarkable, [123I]FP-CIT-SPECT was initiated. Four days prior to the [123I]FP-CIT-SPECT examination the antidepressant treatment was adapted adding bupropion 150 mg/die that was increased to 300 mg/die on the day of [123I]FP-CIT-SPECT. An intravenous bolus injection of ~185 MBq [123I]FP-CIT according to GMP criteria was applied ~1 h after the medication intake and ~3 h before the acquisition of the scans. A three-headed Gamma camera (IRIX 465, Philips Medical System) system was used for SPECT Imaging (3° steps/360°, 60 s per step, 40 frames, pixel size of 3,50 mm, pixel matrix of 128 × 128, LEHR-PAR collimator). OSEM reconstruction (5 subsets, 16 iterations), post-filtering with 3 D Gauss filter (FWHM 7 cm) and Chang's attenuation correction (17) with an attenuation coefficient of 0.15 for all images were performed. [123I]FP-CIT-SPECT was reported pathologic with reductions of striatal DAT binding bilaterally (arrow in Figure 1A) and low contrast between striatal and cortical binding (arrowheads in Figure 1A). The specific binding ratio was calculated using occipital region as a reference (18), and the standard deviations from the reference value mean (Z-score) were calculated using BRASS HERMES software containing age-corrected control population: left caudate nucleus 1.77 (Z-Score −4.2), right caudate 1.81 (Z-Score −3.91), left putamen 1.68 (Z-Score −3.65), and right putamen 1.54 (Z-Score −4.08).
Figure 1 Representative [123I]FP-CIT-SPECT images of the patient. Note inhomogeneous and reduced dopamine transporter binding of the radiopharmaceutical in putamen bilaterally (arrow in A) and low contrast between striatal and cortical binding during short-term bupropion therapy (arrowheads in A), which normalized after a wash-out phase of four half-life periods (arrow and arrowheads in B). Bupropion reduced the binding of [123I]FP-CIT up to 45% (i.e., in right putamen).
Subsequently, consultant neurologist was involved revealing general slowness of movements without true bradykinesia with bilateral reduction of arm pendular movement upon walking. Rigidity was not detected, but active resistance. Importantly, the ongoing therapy with bupropion was noted, whereby the serum blood levels of bupropion (43 ng/ml) and the active metabolite hydroxybupropion (2,332 ng/ml) measured on the day of the neurologic examination were within the therapeutic range. Once the repetition of [123I]FP-CIT SPECT after a wash-out phase was suggested, bupropion was discontinued for 8 days (half-life period 20–37 h). At the day of [123I]FP-CIT-SPECT rescan, the serum blood level for bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml. [123I]FP-CIT SPECT was reported normal (Figure 1B) using the same analysis, with overall normalization of specific binding ratios and Z-scores: left caudate nucleus 3.18 (Z-score −0.2), right caudate nucleus 3.28 (Z-score −0.63), left putamen 3.08 (Z-score −0.51) and right putamen 2.94 (Z-score −0.05).
In the course of the comprehensive differential diagnostics, laboratory tests including blood, urine and cerebrospinal fluid, electroencephalography, and [18F]-FDG PET/CT were performed revealing largely unremarkable results. After degenerative parkinsonism, dementia, autoimmune encephalitis, and other degenerative and inflammatory processes could be excluded, further therapeutic optimization was undertaken. While the antidepressant treatment with venlafaxine and vortioxetine was discontinued, tranylcypromine was initiated after the necessary wash-out phase. While staying on a low-tyramine diet, tranylcypromine was well-tolerated by the patient who partially responded to this treatment adaptation. Subsequently, tranylcypromine was slowly increased up to 50 mg/die. Moreover, the patient received clozapine as additional augmentation treatment that was gradually optimized up to 100 mg/die. Under a treatment regimen including tranylcypromine 50 mg, mirtazapine 30 mg, clozapine 100 mg, aripiprazole 10 mg, and clonazepam 2 mg/die that was accompanied by regular psychotherapeutic-, physiotherapeutic and ergotherapeutic support, a remarkable reduction of her depressive and psychotic symptoms was achieved. The adherent patient showed a total score of 28 at the MADRS and of four at the CGI-S and could be discharged from psychiatric inpatient care. Continuing the abovementioned psychopharmacotherapy she was subsequently treated as outpatient and received psychosocial support at home.
Discussion
The present case report could show effect of blood serum levels of bupropion and its active metabolite hydroxybupropion on [123I]FP-CIT binding to DAT. Hereby, therapeutic doses of bupropion reduced the binding of [123I]FP-CIT ~45–50% throughout the striatum, that was reversible after four half-life periods of bupropion. Since there was no further change in the ongoing therapy, in particular concerning venlafaxine and vortioxetine or mirtazapine, we attribute the observed effect to bupropion. Bupropion is a dose-dependent norepinephrine-dopamine reuptake inhibitor (19), with high occupancy at higher doses. Previous studies suggested changed DAT binding properties in depressed individuals. However, it is still a matter of debate, whether the primary mechanism is down-regulation (19) or up-regulation of DAT (20). Thus, concomitant therapy with bupropion may lead to a significant loss of [123I]FP-CIT binding and hence, might result in false positive diagnosis of degenerative parkinsonism. The [123I]FP-CIT binding pattern in our patient, however, appeared atypical for idiopathic PD and DLB (21), showing a reduced DAT binding throughout the striatum. Indeed, a recent paper noted similar observation, although some asymmetry in [123I]FP-CIT binding in a patient under bupropion therapy was reported (22). Thus, careful visual examination of DAT scan in a patient under dopaminergic medications, such as bupropion, may be critical (5). Taken together, our data suggest, that a discontinuation of bupropion of at least four half-life periods is necessary prior to [123I]FP-CIT scan. However, further prospective studies are needed to examine whether longer discontinuation is necessary, as suggested by some authors (22). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with DAT. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to DAT imaging. This might be of crucial importance especially in patients suffering from late onset depression that was recently related to elevated rates of motor and non-motor symptoms known from degenerative parkinsonian syndromes as well as to altered [123I]FP-CIT binding and, hence, to increased risk of PD and DLB (8).
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
IM and LB were responsible for clinical care and data analysis and drafted the manuscript. KP, DW, and SK supervised clinical care and critically revised the manuscript. TT-W critically revised the manuscript and performed and analyzed [123I]FP-CIT-SPECT scans. All authors contributed to the article and approved the submitted version.
Conflict of Interest
IM received grant from Takeda. LB received travel grants and consultant/speaker honoraria from AOP Orphan, Medizin Medien Austria, Vertretungsnetz, Schwabe Austria, Janssen, and Angelini. KP received honoraria from AOP Orphan Pharmaceuticals, Germania Pharmaceuticals, Lundbeck, and Janssen-Cilag. SK received grants/research support, consulting fees, and/or honoraria from Angelini, AOP Orphan Pharmaceuticals, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. DW received lecture fees/authorship honoraria from Angelini, Lundbeck, and Medizin Medien Austria. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | ARIPIPRAZOLE, BUPROPION, ESKETAMINE, IOFLUPANE I-123, MIRTAZAPINE, VENLAFAXINE HYDROCHLORIDE, VORTIOXETINE | DrugsGivenReaction | CC BY | 33692710 | 19,261,348 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'False positive investigation result'. | Case Report: Bupropion Reduces the [123I]FP-CIT Binding to Striatal Dopamine Transporter.
The diagnosis of parkinsonian syndromes in patients with severe depression may be challenging due to overlapping clinical phenomena, especially regarding psychomotor and affective symptoms. [123I]FP-CIT-SPECT is a useful method to detect degenerative parkinsonian disorders. However, some drugs may influence the tracer binding and thus alter the result. We present a case of 56-year-old female inpatient with difficult-to-treat late-onset depression. Since the current major depressive episode (MDE) was accompanied by psychotic features including delusions and hallucinations as well as hypokinesia, stooped posture and hypomimia, underlying degenerative parkinsonism was suspected. The pathologic [123I]FP-CIT-SPECT scan under ongoing antidepressant therapy with bupropion 300 mg/die (serum level of bupropion 43 ng/ml and hydroxybupropion 2,332 ng/ml) showed reduced [123I]FP-CIT binding throughout the striatum. The scan normalized upon a wash-out phase of four half-time periods (serum level of bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with the dopamine transporter. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to dopamine transporter imaging.
Introduction
The diagnosis of parkinsonian syndromes in patients suffering from severe depression can be challenging. On one hand, these patients may exhibit hypomimia-like facial expression, parkinsonian-like posture or develop psychotic features (1). On the other hand, depression as the most common non-motor symptom in Parkinson's disease (PD) precedes the motor symptoms for ~10 years (2). In doubtful cases, [123I]FP-CIT-SPECT is a useful tool to detect decrease in striatal binding to dopamine transporters (DAT) (3) due to loss of nigrostriatal terminals (4). However, commonly prescribed psychopharmacotherapeutics that bind to DAT may change the binding properties of the tracer (5) and hence, alter the results (6). Although several drugs have been identified, occasionally patients and physicians are not aware that these drugs ought to be paused prior to [123I]FP-CIT-SPECT imaging. This results either in prolonging the diagnostic procedures or, if not considered by specialists, even in imprecise diagnosis. Here we report on a prominent effect of short-term bupropion therapy on [123I]FP-CIT-SPECT imaging.
Case Presentation
The 56-year-old female inpatient (weight: 70 kg, height: 160 cm) had almost a 1-year history of a difficult-to-treat depression (7) with late onset (8). In the course of the current severe major depressive episode (MDE) with psychotic symptoms (International Classification of Diseases, 10th revision, ICD-10 (9): F32.3) that represented her first MDE so far, the patient was anhedonic and exhibited indecisiveness, feelings of hopelessness and worthlessness as well as excessive guilt and diminished ability to concentrate. In the course of her subjective cognitive decline, the patient exhibited a total score of 28/30 at the Mini-Mental State Examination (MMSE) (10) and of 15/18 at the DemTect (11) representing values within the normal range. Furthermore, she suffered from psychomotor slowing, loss of interest and pleasure affecting her hobbies and nearly all activities including the necessary daily routine, as well as delusions and hallucinations. She negated suicidal ideation and there was no suicidal history. The patient showed a total score of 46 at the Montgomery-Åsberg Depression Rating Scale (MADRS) (12) and 6 at the Clinical Global Impressions Scale (CGI-S) (13). In terms of psychiatric and somatic comorbidities, the patient suffered from nicotine dependence (ICD-10: F17.2) and psoriasis vulgaris (ICD-10: L40.0).
The antidepressant combination treatment with mirtazapine 45 mg and venlafaxine 375 mg was expanded with vortioxetine 10 mg/die, but failed to improve the symptoms. Neither augmentation with second-generation antipsychotics (aripiprazole 20 mg/die) (14) and S-ketamine (15) that was administered 2–3 times/week intravenously (up to 50 mg per infusion), nor a series of 11 electroconvulsive therapies (ECT) with subsequent regular maintenance ECTs, all with bilateral stimulation up to 100%, improved the severe depressive symptoms (16).
Due to massive anhedonia, progressive hypomimia, general slowness of movements, delusions and hallucinations, a suspicion of degenerative parkinsonism was raised. Since there were no postural instability and no history of falls, dementia with Lewy bodies (DLB) was considered as a differential diagnosis. While the cranial magnetic resonance imaging was unremarkable, [123I]FP-CIT-SPECT was initiated. Four days prior to the [123I]FP-CIT-SPECT examination the antidepressant treatment was adapted adding bupropion 150 mg/die that was increased to 300 mg/die on the day of [123I]FP-CIT-SPECT. An intravenous bolus injection of ~185 MBq [123I]FP-CIT according to GMP criteria was applied ~1 h after the medication intake and ~3 h before the acquisition of the scans. A three-headed Gamma camera (IRIX 465, Philips Medical System) system was used for SPECT Imaging (3° steps/360°, 60 s per step, 40 frames, pixel size of 3,50 mm, pixel matrix of 128 × 128, LEHR-PAR collimator). OSEM reconstruction (5 subsets, 16 iterations), post-filtering with 3 D Gauss filter (FWHM 7 cm) and Chang's attenuation correction (17) with an attenuation coefficient of 0.15 for all images were performed. [123I]FP-CIT-SPECT was reported pathologic with reductions of striatal DAT binding bilaterally (arrow in Figure 1A) and low contrast between striatal and cortical binding (arrowheads in Figure 1A). The specific binding ratio was calculated using occipital region as a reference (18), and the standard deviations from the reference value mean (Z-score) were calculated using BRASS HERMES software containing age-corrected control population: left caudate nucleus 1.77 (Z-Score −4.2), right caudate 1.81 (Z-Score −3.91), left putamen 1.68 (Z-Score −3.65), and right putamen 1.54 (Z-Score −4.08).
Figure 1 Representative [123I]FP-CIT-SPECT images of the patient. Note inhomogeneous and reduced dopamine transporter binding of the radiopharmaceutical in putamen bilaterally (arrow in A) and low contrast between striatal and cortical binding during short-term bupropion therapy (arrowheads in A), which normalized after a wash-out phase of four half-life periods (arrow and arrowheads in B). Bupropion reduced the binding of [123I]FP-CIT up to 45% (i.e., in right putamen).
Subsequently, consultant neurologist was involved revealing general slowness of movements without true bradykinesia with bilateral reduction of arm pendular movement upon walking. Rigidity was not detected, but active resistance. Importantly, the ongoing therapy with bupropion was noted, whereby the serum blood levels of bupropion (43 ng/ml) and the active metabolite hydroxybupropion (2,332 ng/ml) measured on the day of the neurologic examination were within the therapeutic range. Once the repetition of [123I]FP-CIT SPECT after a wash-out phase was suggested, bupropion was discontinued for 8 days (half-life period 20–37 h). At the day of [123I]FP-CIT-SPECT rescan, the serum blood level for bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml. [123I]FP-CIT SPECT was reported normal (Figure 1B) using the same analysis, with overall normalization of specific binding ratios and Z-scores: left caudate nucleus 3.18 (Z-score −0.2), right caudate nucleus 3.28 (Z-score −0.63), left putamen 3.08 (Z-score −0.51) and right putamen 2.94 (Z-score −0.05).
In the course of the comprehensive differential diagnostics, laboratory tests including blood, urine and cerebrospinal fluid, electroencephalography, and [18F]-FDG PET/CT were performed revealing largely unremarkable results. After degenerative parkinsonism, dementia, autoimmune encephalitis, and other degenerative and inflammatory processes could be excluded, further therapeutic optimization was undertaken. While the antidepressant treatment with venlafaxine and vortioxetine was discontinued, tranylcypromine was initiated after the necessary wash-out phase. While staying on a low-tyramine diet, tranylcypromine was well-tolerated by the patient who partially responded to this treatment adaptation. Subsequently, tranylcypromine was slowly increased up to 50 mg/die. Moreover, the patient received clozapine as additional augmentation treatment that was gradually optimized up to 100 mg/die. Under a treatment regimen including tranylcypromine 50 mg, mirtazapine 30 mg, clozapine 100 mg, aripiprazole 10 mg, and clonazepam 2 mg/die that was accompanied by regular psychotherapeutic-, physiotherapeutic and ergotherapeutic support, a remarkable reduction of her depressive and psychotic symptoms was achieved. The adherent patient showed a total score of 28 at the MADRS and of four at the CGI-S and could be discharged from psychiatric inpatient care. Continuing the abovementioned psychopharmacotherapy she was subsequently treated as outpatient and received psychosocial support at home.
Discussion
The present case report could show effect of blood serum levels of bupropion and its active metabolite hydroxybupropion on [123I]FP-CIT binding to DAT. Hereby, therapeutic doses of bupropion reduced the binding of [123I]FP-CIT ~45–50% throughout the striatum, that was reversible after four half-life periods of bupropion. Since there was no further change in the ongoing therapy, in particular concerning venlafaxine and vortioxetine or mirtazapine, we attribute the observed effect to bupropion. Bupropion is a dose-dependent norepinephrine-dopamine reuptake inhibitor (19), with high occupancy at higher doses. Previous studies suggested changed DAT binding properties in depressed individuals. However, it is still a matter of debate, whether the primary mechanism is down-regulation (19) or up-regulation of DAT (20). Thus, concomitant therapy with bupropion may lead to a significant loss of [123I]FP-CIT binding and hence, might result in false positive diagnosis of degenerative parkinsonism. The [123I]FP-CIT binding pattern in our patient, however, appeared atypical for idiopathic PD and DLB (21), showing a reduced DAT binding throughout the striatum. Indeed, a recent paper noted similar observation, although some asymmetry in [123I]FP-CIT binding in a patient under bupropion therapy was reported (22). Thus, careful visual examination of DAT scan in a patient under dopaminergic medications, such as bupropion, may be critical (5). Taken together, our data suggest, that a discontinuation of bupropion of at least four half-life periods is necessary prior to [123I]FP-CIT scan. However, further prospective studies are needed to examine whether longer discontinuation is necessary, as suggested by some authors (22). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with DAT. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to DAT imaging. This might be of crucial importance especially in patients suffering from late onset depression that was recently related to elevated rates of motor and non-motor symptoms known from degenerative parkinsonian syndromes as well as to altered [123I]FP-CIT binding and, hence, to increased risk of PD and DLB (8).
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
IM and LB were responsible for clinical care and data analysis and drafted the manuscript. KP, DW, and SK supervised clinical care and critically revised the manuscript. TT-W critically revised the manuscript and performed and analyzed [123I]FP-CIT-SPECT scans. All authors contributed to the article and approved the submitted version.
Conflict of Interest
IM received grant from Takeda. LB received travel grants and consultant/speaker honoraria from AOP Orphan, Medizin Medien Austria, Vertretungsnetz, Schwabe Austria, Janssen, and Angelini. KP received honoraria from AOP Orphan Pharmaceuticals, Germania Pharmaceuticals, Lundbeck, and Janssen-Cilag. SK received grants/research support, consulting fees, and/or honoraria from Angelini, AOP Orphan Pharmaceuticals, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. DW received lecture fees/authorship honoraria from Angelini, Lundbeck, and Medizin Medien Austria. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | ARIPIPRAZOLE, BUPROPION, ESKETAMINE, IOFLUPANE I-123, MIRTAZAPINE, VENLAFAXINE HYDROCHLORIDE, VORTIOXETINE | DrugsGivenReaction | CC BY | 33692710 | 19,261,348 | 2021 |
What is the weight of the patient? | Case Report: Bupropion Reduces the [123I]FP-CIT Binding to Striatal Dopamine Transporter.
The diagnosis of parkinsonian syndromes in patients with severe depression may be challenging due to overlapping clinical phenomena, especially regarding psychomotor and affective symptoms. [123I]FP-CIT-SPECT is a useful method to detect degenerative parkinsonian disorders. However, some drugs may influence the tracer binding and thus alter the result. We present a case of 56-year-old female inpatient with difficult-to-treat late-onset depression. Since the current major depressive episode (MDE) was accompanied by psychotic features including delusions and hallucinations as well as hypokinesia, stooped posture and hypomimia, underlying degenerative parkinsonism was suspected. The pathologic [123I]FP-CIT-SPECT scan under ongoing antidepressant therapy with bupropion 300 mg/die (serum level of bupropion 43 ng/ml and hydroxybupropion 2,332 ng/ml) showed reduced [123I]FP-CIT binding throughout the striatum. The scan normalized upon a wash-out phase of four half-time periods (serum level of bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with the dopamine transporter. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to dopamine transporter imaging.
Introduction
The diagnosis of parkinsonian syndromes in patients suffering from severe depression can be challenging. On one hand, these patients may exhibit hypomimia-like facial expression, parkinsonian-like posture or develop psychotic features (1). On the other hand, depression as the most common non-motor symptom in Parkinson's disease (PD) precedes the motor symptoms for ~10 years (2). In doubtful cases, [123I]FP-CIT-SPECT is a useful tool to detect decrease in striatal binding to dopamine transporters (DAT) (3) due to loss of nigrostriatal terminals (4). However, commonly prescribed psychopharmacotherapeutics that bind to DAT may change the binding properties of the tracer (5) and hence, alter the results (6). Although several drugs have been identified, occasionally patients and physicians are not aware that these drugs ought to be paused prior to [123I]FP-CIT-SPECT imaging. This results either in prolonging the diagnostic procedures or, if not considered by specialists, even in imprecise diagnosis. Here we report on a prominent effect of short-term bupropion therapy on [123I]FP-CIT-SPECT imaging.
Case Presentation
The 56-year-old female inpatient (weight: 70 kg, height: 160 cm) had almost a 1-year history of a difficult-to-treat depression (7) with late onset (8). In the course of the current severe major depressive episode (MDE) with psychotic symptoms (International Classification of Diseases, 10th revision, ICD-10 (9): F32.3) that represented her first MDE so far, the patient was anhedonic and exhibited indecisiveness, feelings of hopelessness and worthlessness as well as excessive guilt and diminished ability to concentrate. In the course of her subjective cognitive decline, the patient exhibited a total score of 28/30 at the Mini-Mental State Examination (MMSE) (10) and of 15/18 at the DemTect (11) representing values within the normal range. Furthermore, she suffered from psychomotor slowing, loss of interest and pleasure affecting her hobbies and nearly all activities including the necessary daily routine, as well as delusions and hallucinations. She negated suicidal ideation and there was no suicidal history. The patient showed a total score of 46 at the Montgomery-Åsberg Depression Rating Scale (MADRS) (12) and 6 at the Clinical Global Impressions Scale (CGI-S) (13). In terms of psychiatric and somatic comorbidities, the patient suffered from nicotine dependence (ICD-10: F17.2) and psoriasis vulgaris (ICD-10: L40.0).
The antidepressant combination treatment with mirtazapine 45 mg and venlafaxine 375 mg was expanded with vortioxetine 10 mg/die, but failed to improve the symptoms. Neither augmentation with second-generation antipsychotics (aripiprazole 20 mg/die) (14) and S-ketamine (15) that was administered 2–3 times/week intravenously (up to 50 mg per infusion), nor a series of 11 electroconvulsive therapies (ECT) with subsequent regular maintenance ECTs, all with bilateral stimulation up to 100%, improved the severe depressive symptoms (16).
Due to massive anhedonia, progressive hypomimia, general slowness of movements, delusions and hallucinations, a suspicion of degenerative parkinsonism was raised. Since there were no postural instability and no history of falls, dementia with Lewy bodies (DLB) was considered as a differential diagnosis. While the cranial magnetic resonance imaging was unremarkable, [123I]FP-CIT-SPECT was initiated. Four days prior to the [123I]FP-CIT-SPECT examination the antidepressant treatment was adapted adding bupropion 150 mg/die that was increased to 300 mg/die on the day of [123I]FP-CIT-SPECT. An intravenous bolus injection of ~185 MBq [123I]FP-CIT according to GMP criteria was applied ~1 h after the medication intake and ~3 h before the acquisition of the scans. A three-headed Gamma camera (IRIX 465, Philips Medical System) system was used for SPECT Imaging (3° steps/360°, 60 s per step, 40 frames, pixel size of 3,50 mm, pixel matrix of 128 × 128, LEHR-PAR collimator). OSEM reconstruction (5 subsets, 16 iterations), post-filtering with 3 D Gauss filter (FWHM 7 cm) and Chang's attenuation correction (17) with an attenuation coefficient of 0.15 for all images were performed. [123I]FP-CIT-SPECT was reported pathologic with reductions of striatal DAT binding bilaterally (arrow in Figure 1A) and low contrast between striatal and cortical binding (arrowheads in Figure 1A). The specific binding ratio was calculated using occipital region as a reference (18), and the standard deviations from the reference value mean (Z-score) were calculated using BRASS HERMES software containing age-corrected control population: left caudate nucleus 1.77 (Z-Score −4.2), right caudate 1.81 (Z-Score −3.91), left putamen 1.68 (Z-Score −3.65), and right putamen 1.54 (Z-Score −4.08).
Figure 1 Representative [123I]FP-CIT-SPECT images of the patient. Note inhomogeneous and reduced dopamine transporter binding of the radiopharmaceutical in putamen bilaterally (arrow in A) and low contrast between striatal and cortical binding during short-term bupropion therapy (arrowheads in A), which normalized after a wash-out phase of four half-life periods (arrow and arrowheads in B). Bupropion reduced the binding of [123I]FP-CIT up to 45% (i.e., in right putamen).
Subsequently, consultant neurologist was involved revealing general slowness of movements without true bradykinesia with bilateral reduction of arm pendular movement upon walking. Rigidity was not detected, but active resistance. Importantly, the ongoing therapy with bupropion was noted, whereby the serum blood levels of bupropion (43 ng/ml) and the active metabolite hydroxybupropion (2,332 ng/ml) measured on the day of the neurologic examination were within the therapeutic range. Once the repetition of [123I]FP-CIT SPECT after a wash-out phase was suggested, bupropion was discontinued for 8 days (half-life period 20–37 h). At the day of [123I]FP-CIT-SPECT rescan, the serum blood level for bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml. [123I]FP-CIT SPECT was reported normal (Figure 1B) using the same analysis, with overall normalization of specific binding ratios and Z-scores: left caudate nucleus 3.18 (Z-score −0.2), right caudate nucleus 3.28 (Z-score −0.63), left putamen 3.08 (Z-score −0.51) and right putamen 2.94 (Z-score −0.05).
In the course of the comprehensive differential diagnostics, laboratory tests including blood, urine and cerebrospinal fluid, electroencephalography, and [18F]-FDG PET/CT were performed revealing largely unremarkable results. After degenerative parkinsonism, dementia, autoimmune encephalitis, and other degenerative and inflammatory processes could be excluded, further therapeutic optimization was undertaken. While the antidepressant treatment with venlafaxine and vortioxetine was discontinued, tranylcypromine was initiated after the necessary wash-out phase. While staying on a low-tyramine diet, tranylcypromine was well-tolerated by the patient who partially responded to this treatment adaptation. Subsequently, tranylcypromine was slowly increased up to 50 mg/die. Moreover, the patient received clozapine as additional augmentation treatment that was gradually optimized up to 100 mg/die. Under a treatment regimen including tranylcypromine 50 mg, mirtazapine 30 mg, clozapine 100 mg, aripiprazole 10 mg, and clonazepam 2 mg/die that was accompanied by regular psychotherapeutic-, physiotherapeutic and ergotherapeutic support, a remarkable reduction of her depressive and psychotic symptoms was achieved. The adherent patient showed a total score of 28 at the MADRS and of four at the CGI-S and could be discharged from psychiatric inpatient care. Continuing the abovementioned psychopharmacotherapy she was subsequently treated as outpatient and received psychosocial support at home.
Discussion
The present case report could show effect of blood serum levels of bupropion and its active metabolite hydroxybupropion on [123I]FP-CIT binding to DAT. Hereby, therapeutic doses of bupropion reduced the binding of [123I]FP-CIT ~45–50% throughout the striatum, that was reversible after four half-life periods of bupropion. Since there was no further change in the ongoing therapy, in particular concerning venlafaxine and vortioxetine or mirtazapine, we attribute the observed effect to bupropion. Bupropion is a dose-dependent norepinephrine-dopamine reuptake inhibitor (19), with high occupancy at higher doses. Previous studies suggested changed DAT binding properties in depressed individuals. However, it is still a matter of debate, whether the primary mechanism is down-regulation (19) or up-regulation of DAT (20). Thus, concomitant therapy with bupropion may lead to a significant loss of [123I]FP-CIT binding and hence, might result in false positive diagnosis of degenerative parkinsonism. The [123I]FP-CIT binding pattern in our patient, however, appeared atypical for idiopathic PD and DLB (21), showing a reduced DAT binding throughout the striatum. Indeed, a recent paper noted similar observation, although some asymmetry in [123I]FP-CIT binding in a patient under bupropion therapy was reported (22). Thus, careful visual examination of DAT scan in a patient under dopaminergic medications, such as bupropion, may be critical (5). Taken together, our data suggest, that a discontinuation of bupropion of at least four half-life periods is necessary prior to [123I]FP-CIT scan. However, further prospective studies are needed to examine whether longer discontinuation is necessary, as suggested by some authors (22). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with DAT. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to DAT imaging. This might be of crucial importance especially in patients suffering from late onset depression that was recently related to elevated rates of motor and non-motor symptoms known from degenerative parkinsonian syndromes as well as to altered [123I]FP-CIT binding and, hence, to increased risk of PD and DLB (8).
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
IM and LB were responsible for clinical care and data analysis and drafted the manuscript. KP, DW, and SK supervised clinical care and critically revised the manuscript. TT-W critically revised the manuscript and performed and analyzed [123I]FP-CIT-SPECT scans. All authors contributed to the article and approved the submitted version.
Conflict of Interest
IM received grant from Takeda. LB received travel grants and consultant/speaker honoraria from AOP Orphan, Medizin Medien Austria, Vertretungsnetz, Schwabe Austria, Janssen, and Angelini. KP received honoraria from AOP Orphan Pharmaceuticals, Germania Pharmaceuticals, Lundbeck, and Janssen-Cilag. SK received grants/research support, consulting fees, and/or honoraria from Angelini, AOP Orphan Pharmaceuticals, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. DW received lecture fees/authorship honoraria from Angelini, Lundbeck, and Medizin Medien Austria. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 70 kg. | Weight | CC BY | 33692710 | 19,261,348 | 2021 |
What was the administration route of drug 'IOFLUPANE I-123'? | Case Report: Bupropion Reduces the [123I]FP-CIT Binding to Striatal Dopamine Transporter.
The diagnosis of parkinsonian syndromes in patients with severe depression may be challenging due to overlapping clinical phenomena, especially regarding psychomotor and affective symptoms. [123I]FP-CIT-SPECT is a useful method to detect degenerative parkinsonian disorders. However, some drugs may influence the tracer binding and thus alter the result. We present a case of 56-year-old female inpatient with difficult-to-treat late-onset depression. Since the current major depressive episode (MDE) was accompanied by psychotic features including delusions and hallucinations as well as hypokinesia, stooped posture and hypomimia, underlying degenerative parkinsonism was suspected. The pathologic [123I]FP-CIT-SPECT scan under ongoing antidepressant therapy with bupropion 300 mg/die (serum level of bupropion 43 ng/ml and hydroxybupropion 2,332 ng/ml) showed reduced [123I]FP-CIT binding throughout the striatum. The scan normalized upon a wash-out phase of four half-time periods (serum level of bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with the dopamine transporter. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to dopamine transporter imaging.
Introduction
The diagnosis of parkinsonian syndromes in patients suffering from severe depression can be challenging. On one hand, these patients may exhibit hypomimia-like facial expression, parkinsonian-like posture or develop psychotic features (1). On the other hand, depression as the most common non-motor symptom in Parkinson's disease (PD) precedes the motor symptoms for ~10 years (2). In doubtful cases, [123I]FP-CIT-SPECT is a useful tool to detect decrease in striatal binding to dopamine transporters (DAT) (3) due to loss of nigrostriatal terminals (4). However, commonly prescribed psychopharmacotherapeutics that bind to DAT may change the binding properties of the tracer (5) and hence, alter the results (6). Although several drugs have been identified, occasionally patients and physicians are not aware that these drugs ought to be paused prior to [123I]FP-CIT-SPECT imaging. This results either in prolonging the diagnostic procedures or, if not considered by specialists, even in imprecise diagnosis. Here we report on a prominent effect of short-term bupropion therapy on [123I]FP-CIT-SPECT imaging.
Case Presentation
The 56-year-old female inpatient (weight: 70 kg, height: 160 cm) had almost a 1-year history of a difficult-to-treat depression (7) with late onset (8). In the course of the current severe major depressive episode (MDE) with psychotic symptoms (International Classification of Diseases, 10th revision, ICD-10 (9): F32.3) that represented her first MDE so far, the patient was anhedonic and exhibited indecisiveness, feelings of hopelessness and worthlessness as well as excessive guilt and diminished ability to concentrate. In the course of her subjective cognitive decline, the patient exhibited a total score of 28/30 at the Mini-Mental State Examination (MMSE) (10) and of 15/18 at the DemTect (11) representing values within the normal range. Furthermore, she suffered from psychomotor slowing, loss of interest and pleasure affecting her hobbies and nearly all activities including the necessary daily routine, as well as delusions and hallucinations. She negated suicidal ideation and there was no suicidal history. The patient showed a total score of 46 at the Montgomery-Åsberg Depression Rating Scale (MADRS) (12) and 6 at the Clinical Global Impressions Scale (CGI-S) (13). In terms of psychiatric and somatic comorbidities, the patient suffered from nicotine dependence (ICD-10: F17.2) and psoriasis vulgaris (ICD-10: L40.0).
The antidepressant combination treatment with mirtazapine 45 mg and venlafaxine 375 mg was expanded with vortioxetine 10 mg/die, but failed to improve the symptoms. Neither augmentation with second-generation antipsychotics (aripiprazole 20 mg/die) (14) and S-ketamine (15) that was administered 2–3 times/week intravenously (up to 50 mg per infusion), nor a series of 11 electroconvulsive therapies (ECT) with subsequent regular maintenance ECTs, all with bilateral stimulation up to 100%, improved the severe depressive symptoms (16).
Due to massive anhedonia, progressive hypomimia, general slowness of movements, delusions and hallucinations, a suspicion of degenerative parkinsonism was raised. Since there were no postural instability and no history of falls, dementia with Lewy bodies (DLB) was considered as a differential diagnosis. While the cranial magnetic resonance imaging was unremarkable, [123I]FP-CIT-SPECT was initiated. Four days prior to the [123I]FP-CIT-SPECT examination the antidepressant treatment was adapted adding bupropion 150 mg/die that was increased to 300 mg/die on the day of [123I]FP-CIT-SPECT. An intravenous bolus injection of ~185 MBq [123I]FP-CIT according to GMP criteria was applied ~1 h after the medication intake and ~3 h before the acquisition of the scans. A three-headed Gamma camera (IRIX 465, Philips Medical System) system was used for SPECT Imaging (3° steps/360°, 60 s per step, 40 frames, pixel size of 3,50 mm, pixel matrix of 128 × 128, LEHR-PAR collimator). OSEM reconstruction (5 subsets, 16 iterations), post-filtering with 3 D Gauss filter (FWHM 7 cm) and Chang's attenuation correction (17) with an attenuation coefficient of 0.15 for all images were performed. [123I]FP-CIT-SPECT was reported pathologic with reductions of striatal DAT binding bilaterally (arrow in Figure 1A) and low contrast between striatal and cortical binding (arrowheads in Figure 1A). The specific binding ratio was calculated using occipital region as a reference (18), and the standard deviations from the reference value mean (Z-score) were calculated using BRASS HERMES software containing age-corrected control population: left caudate nucleus 1.77 (Z-Score −4.2), right caudate 1.81 (Z-Score −3.91), left putamen 1.68 (Z-Score −3.65), and right putamen 1.54 (Z-Score −4.08).
Figure 1 Representative [123I]FP-CIT-SPECT images of the patient. Note inhomogeneous and reduced dopamine transporter binding of the radiopharmaceutical in putamen bilaterally (arrow in A) and low contrast between striatal and cortical binding during short-term bupropion therapy (arrowheads in A), which normalized after a wash-out phase of four half-life periods (arrow and arrowheads in B). Bupropion reduced the binding of [123I]FP-CIT up to 45% (i.e., in right putamen).
Subsequently, consultant neurologist was involved revealing general slowness of movements without true bradykinesia with bilateral reduction of arm pendular movement upon walking. Rigidity was not detected, but active resistance. Importantly, the ongoing therapy with bupropion was noted, whereby the serum blood levels of bupropion (43 ng/ml) and the active metabolite hydroxybupropion (2,332 ng/ml) measured on the day of the neurologic examination were within the therapeutic range. Once the repetition of [123I]FP-CIT SPECT after a wash-out phase was suggested, bupropion was discontinued for 8 days (half-life period 20–37 h). At the day of [123I]FP-CIT-SPECT rescan, the serum blood level for bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml. [123I]FP-CIT SPECT was reported normal (Figure 1B) using the same analysis, with overall normalization of specific binding ratios and Z-scores: left caudate nucleus 3.18 (Z-score −0.2), right caudate nucleus 3.28 (Z-score −0.63), left putamen 3.08 (Z-score −0.51) and right putamen 2.94 (Z-score −0.05).
In the course of the comprehensive differential diagnostics, laboratory tests including blood, urine and cerebrospinal fluid, electroencephalography, and [18F]-FDG PET/CT were performed revealing largely unremarkable results. After degenerative parkinsonism, dementia, autoimmune encephalitis, and other degenerative and inflammatory processes could be excluded, further therapeutic optimization was undertaken. While the antidepressant treatment with venlafaxine and vortioxetine was discontinued, tranylcypromine was initiated after the necessary wash-out phase. While staying on a low-tyramine diet, tranylcypromine was well-tolerated by the patient who partially responded to this treatment adaptation. Subsequently, tranylcypromine was slowly increased up to 50 mg/die. Moreover, the patient received clozapine as additional augmentation treatment that was gradually optimized up to 100 mg/die. Under a treatment regimen including tranylcypromine 50 mg, mirtazapine 30 mg, clozapine 100 mg, aripiprazole 10 mg, and clonazepam 2 mg/die that was accompanied by regular psychotherapeutic-, physiotherapeutic and ergotherapeutic support, a remarkable reduction of her depressive and psychotic symptoms was achieved. The adherent patient showed a total score of 28 at the MADRS and of four at the CGI-S and could be discharged from psychiatric inpatient care. Continuing the abovementioned psychopharmacotherapy she was subsequently treated as outpatient and received psychosocial support at home.
Discussion
The present case report could show effect of blood serum levels of bupropion and its active metabolite hydroxybupropion on [123I]FP-CIT binding to DAT. Hereby, therapeutic doses of bupropion reduced the binding of [123I]FP-CIT ~45–50% throughout the striatum, that was reversible after four half-life periods of bupropion. Since there was no further change in the ongoing therapy, in particular concerning venlafaxine and vortioxetine or mirtazapine, we attribute the observed effect to bupropion. Bupropion is a dose-dependent norepinephrine-dopamine reuptake inhibitor (19), with high occupancy at higher doses. Previous studies suggested changed DAT binding properties in depressed individuals. However, it is still a matter of debate, whether the primary mechanism is down-regulation (19) or up-regulation of DAT (20). Thus, concomitant therapy with bupropion may lead to a significant loss of [123I]FP-CIT binding and hence, might result in false positive diagnosis of degenerative parkinsonism. The [123I]FP-CIT binding pattern in our patient, however, appeared atypical for idiopathic PD and DLB (21), showing a reduced DAT binding throughout the striatum. Indeed, a recent paper noted similar observation, although some asymmetry in [123I]FP-CIT binding in a patient under bupropion therapy was reported (22). Thus, careful visual examination of DAT scan in a patient under dopaminergic medications, such as bupropion, may be critical (5). Taken together, our data suggest, that a discontinuation of bupropion of at least four half-life periods is necessary prior to [123I]FP-CIT scan. However, further prospective studies are needed to examine whether longer discontinuation is necessary, as suggested by some authors (22). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with DAT. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to DAT imaging. This might be of crucial importance especially in patients suffering from late onset depression that was recently related to elevated rates of motor and non-motor symptoms known from degenerative parkinsonian syndromes as well as to altered [123I]FP-CIT binding and, hence, to increased risk of PD and DLB (8).
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
IM and LB were responsible for clinical care and data analysis and drafted the manuscript. KP, DW, and SK supervised clinical care and critically revised the manuscript. TT-W critically revised the manuscript and performed and analyzed [123I]FP-CIT-SPECT scans. All authors contributed to the article and approved the submitted version.
Conflict of Interest
IM received grant from Takeda. LB received travel grants and consultant/speaker honoraria from AOP Orphan, Medizin Medien Austria, Vertretungsnetz, Schwabe Austria, Janssen, and Angelini. KP received honoraria from AOP Orphan Pharmaceuticals, Germania Pharmaceuticals, Lundbeck, and Janssen-Cilag. SK received grants/research support, consulting fees, and/or honoraria from Angelini, AOP Orphan Pharmaceuticals, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. DW received lecture fees/authorship honoraria from Angelini, Lundbeck, and Medizin Medien Austria. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Intravenous bolus | DrugAdministrationRoute | CC BY | 33692710 | 19,253,442 | 2021 |
What was the dosage of drug 'IOFLUPANE I-123'? | Case Report: Bupropion Reduces the [123I]FP-CIT Binding to Striatal Dopamine Transporter.
The diagnosis of parkinsonian syndromes in patients with severe depression may be challenging due to overlapping clinical phenomena, especially regarding psychomotor and affective symptoms. [123I]FP-CIT-SPECT is a useful method to detect degenerative parkinsonian disorders. However, some drugs may influence the tracer binding and thus alter the result. We present a case of 56-year-old female inpatient with difficult-to-treat late-onset depression. Since the current major depressive episode (MDE) was accompanied by psychotic features including delusions and hallucinations as well as hypokinesia, stooped posture and hypomimia, underlying degenerative parkinsonism was suspected. The pathologic [123I]FP-CIT-SPECT scan under ongoing antidepressant therapy with bupropion 300 mg/die (serum level of bupropion 43 ng/ml and hydroxybupropion 2,332 ng/ml) showed reduced [123I]FP-CIT binding throughout the striatum. The scan normalized upon a wash-out phase of four half-time periods (serum level of bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with the dopamine transporter. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to dopamine transporter imaging.
Introduction
The diagnosis of parkinsonian syndromes in patients suffering from severe depression can be challenging. On one hand, these patients may exhibit hypomimia-like facial expression, parkinsonian-like posture or develop psychotic features (1). On the other hand, depression as the most common non-motor symptom in Parkinson's disease (PD) precedes the motor symptoms for ~10 years (2). In doubtful cases, [123I]FP-CIT-SPECT is a useful tool to detect decrease in striatal binding to dopamine transporters (DAT) (3) due to loss of nigrostriatal terminals (4). However, commonly prescribed psychopharmacotherapeutics that bind to DAT may change the binding properties of the tracer (5) and hence, alter the results (6). Although several drugs have been identified, occasionally patients and physicians are not aware that these drugs ought to be paused prior to [123I]FP-CIT-SPECT imaging. This results either in prolonging the diagnostic procedures or, if not considered by specialists, even in imprecise diagnosis. Here we report on a prominent effect of short-term bupropion therapy on [123I]FP-CIT-SPECT imaging.
Case Presentation
The 56-year-old female inpatient (weight: 70 kg, height: 160 cm) had almost a 1-year history of a difficult-to-treat depression (7) with late onset (8). In the course of the current severe major depressive episode (MDE) with psychotic symptoms (International Classification of Diseases, 10th revision, ICD-10 (9): F32.3) that represented her first MDE so far, the patient was anhedonic and exhibited indecisiveness, feelings of hopelessness and worthlessness as well as excessive guilt and diminished ability to concentrate. In the course of her subjective cognitive decline, the patient exhibited a total score of 28/30 at the Mini-Mental State Examination (MMSE) (10) and of 15/18 at the DemTect (11) representing values within the normal range. Furthermore, she suffered from psychomotor slowing, loss of interest and pleasure affecting her hobbies and nearly all activities including the necessary daily routine, as well as delusions and hallucinations. She negated suicidal ideation and there was no suicidal history. The patient showed a total score of 46 at the Montgomery-Åsberg Depression Rating Scale (MADRS) (12) and 6 at the Clinical Global Impressions Scale (CGI-S) (13). In terms of psychiatric and somatic comorbidities, the patient suffered from nicotine dependence (ICD-10: F17.2) and psoriasis vulgaris (ICD-10: L40.0).
The antidepressant combination treatment with mirtazapine 45 mg and venlafaxine 375 mg was expanded with vortioxetine 10 mg/die, but failed to improve the symptoms. Neither augmentation with second-generation antipsychotics (aripiprazole 20 mg/die) (14) and S-ketamine (15) that was administered 2–3 times/week intravenously (up to 50 mg per infusion), nor a series of 11 electroconvulsive therapies (ECT) with subsequent regular maintenance ECTs, all with bilateral stimulation up to 100%, improved the severe depressive symptoms (16).
Due to massive anhedonia, progressive hypomimia, general slowness of movements, delusions and hallucinations, a suspicion of degenerative parkinsonism was raised. Since there were no postural instability and no history of falls, dementia with Lewy bodies (DLB) was considered as a differential diagnosis. While the cranial magnetic resonance imaging was unremarkable, [123I]FP-CIT-SPECT was initiated. Four days prior to the [123I]FP-CIT-SPECT examination the antidepressant treatment was adapted adding bupropion 150 mg/die that was increased to 300 mg/die on the day of [123I]FP-CIT-SPECT. An intravenous bolus injection of ~185 MBq [123I]FP-CIT according to GMP criteria was applied ~1 h after the medication intake and ~3 h before the acquisition of the scans. A three-headed Gamma camera (IRIX 465, Philips Medical System) system was used for SPECT Imaging (3° steps/360°, 60 s per step, 40 frames, pixel size of 3,50 mm, pixel matrix of 128 × 128, LEHR-PAR collimator). OSEM reconstruction (5 subsets, 16 iterations), post-filtering with 3 D Gauss filter (FWHM 7 cm) and Chang's attenuation correction (17) with an attenuation coefficient of 0.15 for all images were performed. [123I]FP-CIT-SPECT was reported pathologic with reductions of striatal DAT binding bilaterally (arrow in Figure 1A) and low contrast between striatal and cortical binding (arrowheads in Figure 1A). The specific binding ratio was calculated using occipital region as a reference (18), and the standard deviations from the reference value mean (Z-score) were calculated using BRASS HERMES software containing age-corrected control population: left caudate nucleus 1.77 (Z-Score −4.2), right caudate 1.81 (Z-Score −3.91), left putamen 1.68 (Z-Score −3.65), and right putamen 1.54 (Z-Score −4.08).
Figure 1 Representative [123I]FP-CIT-SPECT images of the patient. Note inhomogeneous and reduced dopamine transporter binding of the radiopharmaceutical in putamen bilaterally (arrow in A) and low contrast between striatal and cortical binding during short-term bupropion therapy (arrowheads in A), which normalized after a wash-out phase of four half-life periods (arrow and arrowheads in B). Bupropion reduced the binding of [123I]FP-CIT up to 45% (i.e., in right putamen).
Subsequently, consultant neurologist was involved revealing general slowness of movements without true bradykinesia with bilateral reduction of arm pendular movement upon walking. Rigidity was not detected, but active resistance. Importantly, the ongoing therapy with bupropion was noted, whereby the serum blood levels of bupropion (43 ng/ml) and the active metabolite hydroxybupropion (2,332 ng/ml) measured on the day of the neurologic examination were within the therapeutic range. Once the repetition of [123I]FP-CIT SPECT after a wash-out phase was suggested, bupropion was discontinued for 8 days (half-life period 20–37 h). At the day of [123I]FP-CIT-SPECT rescan, the serum blood level for bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml. [123I]FP-CIT SPECT was reported normal (Figure 1B) using the same analysis, with overall normalization of specific binding ratios and Z-scores: left caudate nucleus 3.18 (Z-score −0.2), right caudate nucleus 3.28 (Z-score −0.63), left putamen 3.08 (Z-score −0.51) and right putamen 2.94 (Z-score −0.05).
In the course of the comprehensive differential diagnostics, laboratory tests including blood, urine and cerebrospinal fluid, electroencephalography, and [18F]-FDG PET/CT were performed revealing largely unremarkable results. After degenerative parkinsonism, dementia, autoimmune encephalitis, and other degenerative and inflammatory processes could be excluded, further therapeutic optimization was undertaken. While the antidepressant treatment with venlafaxine and vortioxetine was discontinued, tranylcypromine was initiated after the necessary wash-out phase. While staying on a low-tyramine diet, tranylcypromine was well-tolerated by the patient who partially responded to this treatment adaptation. Subsequently, tranylcypromine was slowly increased up to 50 mg/die. Moreover, the patient received clozapine as additional augmentation treatment that was gradually optimized up to 100 mg/die. Under a treatment regimen including tranylcypromine 50 mg, mirtazapine 30 mg, clozapine 100 mg, aripiprazole 10 mg, and clonazepam 2 mg/die that was accompanied by regular psychotherapeutic-, physiotherapeutic and ergotherapeutic support, a remarkable reduction of her depressive and psychotic symptoms was achieved. The adherent patient showed a total score of 28 at the MADRS and of four at the CGI-S and could be discharged from psychiatric inpatient care. Continuing the abovementioned psychopharmacotherapy she was subsequently treated as outpatient and received psychosocial support at home.
Discussion
The present case report could show effect of blood serum levels of bupropion and its active metabolite hydroxybupropion on [123I]FP-CIT binding to DAT. Hereby, therapeutic doses of bupropion reduced the binding of [123I]FP-CIT ~45–50% throughout the striatum, that was reversible after four half-life periods of bupropion. Since there was no further change in the ongoing therapy, in particular concerning venlafaxine and vortioxetine or mirtazapine, we attribute the observed effect to bupropion. Bupropion is a dose-dependent norepinephrine-dopamine reuptake inhibitor (19), with high occupancy at higher doses. Previous studies suggested changed DAT binding properties in depressed individuals. However, it is still a matter of debate, whether the primary mechanism is down-regulation (19) or up-regulation of DAT (20). Thus, concomitant therapy with bupropion may lead to a significant loss of [123I]FP-CIT binding and hence, might result in false positive diagnosis of degenerative parkinsonism. The [123I]FP-CIT binding pattern in our patient, however, appeared atypical for idiopathic PD and DLB (21), showing a reduced DAT binding throughout the striatum. Indeed, a recent paper noted similar observation, although some asymmetry in [123I]FP-CIT binding in a patient under bupropion therapy was reported (22). Thus, careful visual examination of DAT scan in a patient under dopaminergic medications, such as bupropion, may be critical (5). Taken together, our data suggest, that a discontinuation of bupropion of at least four half-life periods is necessary prior to [123I]FP-CIT scan. However, further prospective studies are needed to examine whether longer discontinuation is necessary, as suggested by some authors (22). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with DAT. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to DAT imaging. This might be of crucial importance especially in patients suffering from late onset depression that was recently related to elevated rates of motor and non-motor symptoms known from degenerative parkinsonian syndromes as well as to altered [123I]FP-CIT binding and, hence, to increased risk of PD and DLB (8).
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
IM and LB were responsible for clinical care and data analysis and drafted the manuscript. KP, DW, and SK supervised clinical care and critically revised the manuscript. TT-W critically revised the manuscript and performed and analyzed [123I]FP-CIT-SPECT scans. All authors contributed to the article and approved the submitted version.
Conflict of Interest
IM received grant from Takeda. LB received travel grants and consultant/speaker honoraria from AOP Orphan, Medizin Medien Austria, Vertretungsnetz, Schwabe Austria, Janssen, and Angelini. KP received honoraria from AOP Orphan Pharmaceuticals, Germania Pharmaceuticals, Lundbeck, and Janssen-Cilag. SK received grants/research support, consulting fees, and/or honoraria from Angelini, AOP Orphan Pharmaceuticals, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. DW received lecture fees/authorship honoraria from Angelini, Lundbeck, and Medizin Medien Austria. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | APPROX 185 MBQ [123I]FP?CIT | DrugDosageText | CC BY | 33692710 | 19,261,348 | 2021 |
What was the dosage of drug 'VENLAFAXINE HYDROCHLORIDE'? | Case Report: Bupropion Reduces the [123I]FP-CIT Binding to Striatal Dopamine Transporter.
The diagnosis of parkinsonian syndromes in patients with severe depression may be challenging due to overlapping clinical phenomena, especially regarding psychomotor and affective symptoms. [123I]FP-CIT-SPECT is a useful method to detect degenerative parkinsonian disorders. However, some drugs may influence the tracer binding and thus alter the result. We present a case of 56-year-old female inpatient with difficult-to-treat late-onset depression. Since the current major depressive episode (MDE) was accompanied by psychotic features including delusions and hallucinations as well as hypokinesia, stooped posture and hypomimia, underlying degenerative parkinsonism was suspected. The pathologic [123I]FP-CIT-SPECT scan under ongoing antidepressant therapy with bupropion 300 mg/die (serum level of bupropion 43 ng/ml and hydroxybupropion 2,332 ng/ml) showed reduced [123I]FP-CIT binding throughout the striatum. The scan normalized upon a wash-out phase of four half-time periods (serum level of bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with the dopamine transporter. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to dopamine transporter imaging.
Introduction
The diagnosis of parkinsonian syndromes in patients suffering from severe depression can be challenging. On one hand, these patients may exhibit hypomimia-like facial expression, parkinsonian-like posture or develop psychotic features (1). On the other hand, depression as the most common non-motor symptom in Parkinson's disease (PD) precedes the motor symptoms for ~10 years (2). In doubtful cases, [123I]FP-CIT-SPECT is a useful tool to detect decrease in striatal binding to dopamine transporters (DAT) (3) due to loss of nigrostriatal terminals (4). However, commonly prescribed psychopharmacotherapeutics that bind to DAT may change the binding properties of the tracer (5) and hence, alter the results (6). Although several drugs have been identified, occasionally patients and physicians are not aware that these drugs ought to be paused prior to [123I]FP-CIT-SPECT imaging. This results either in prolonging the diagnostic procedures or, if not considered by specialists, even in imprecise diagnosis. Here we report on a prominent effect of short-term bupropion therapy on [123I]FP-CIT-SPECT imaging.
Case Presentation
The 56-year-old female inpatient (weight: 70 kg, height: 160 cm) had almost a 1-year history of a difficult-to-treat depression (7) with late onset (8). In the course of the current severe major depressive episode (MDE) with psychotic symptoms (International Classification of Diseases, 10th revision, ICD-10 (9): F32.3) that represented her first MDE so far, the patient was anhedonic and exhibited indecisiveness, feelings of hopelessness and worthlessness as well as excessive guilt and diminished ability to concentrate. In the course of her subjective cognitive decline, the patient exhibited a total score of 28/30 at the Mini-Mental State Examination (MMSE) (10) and of 15/18 at the DemTect (11) representing values within the normal range. Furthermore, she suffered from psychomotor slowing, loss of interest and pleasure affecting her hobbies and nearly all activities including the necessary daily routine, as well as delusions and hallucinations. She negated suicidal ideation and there was no suicidal history. The patient showed a total score of 46 at the Montgomery-Åsberg Depression Rating Scale (MADRS) (12) and 6 at the Clinical Global Impressions Scale (CGI-S) (13). In terms of psychiatric and somatic comorbidities, the patient suffered from nicotine dependence (ICD-10: F17.2) and psoriasis vulgaris (ICD-10: L40.0).
The antidepressant combination treatment with mirtazapine 45 mg and venlafaxine 375 mg was expanded with vortioxetine 10 mg/die, but failed to improve the symptoms. Neither augmentation with second-generation antipsychotics (aripiprazole 20 mg/die) (14) and S-ketamine (15) that was administered 2–3 times/week intravenously (up to 50 mg per infusion), nor a series of 11 electroconvulsive therapies (ECT) with subsequent regular maintenance ECTs, all with bilateral stimulation up to 100%, improved the severe depressive symptoms (16).
Due to massive anhedonia, progressive hypomimia, general slowness of movements, delusions and hallucinations, a suspicion of degenerative parkinsonism was raised. Since there were no postural instability and no history of falls, dementia with Lewy bodies (DLB) was considered as a differential diagnosis. While the cranial magnetic resonance imaging was unremarkable, [123I]FP-CIT-SPECT was initiated. Four days prior to the [123I]FP-CIT-SPECT examination the antidepressant treatment was adapted adding bupropion 150 mg/die that was increased to 300 mg/die on the day of [123I]FP-CIT-SPECT. An intravenous bolus injection of ~185 MBq [123I]FP-CIT according to GMP criteria was applied ~1 h after the medication intake and ~3 h before the acquisition of the scans. A three-headed Gamma camera (IRIX 465, Philips Medical System) system was used for SPECT Imaging (3° steps/360°, 60 s per step, 40 frames, pixel size of 3,50 mm, pixel matrix of 128 × 128, LEHR-PAR collimator). OSEM reconstruction (5 subsets, 16 iterations), post-filtering with 3 D Gauss filter (FWHM 7 cm) and Chang's attenuation correction (17) with an attenuation coefficient of 0.15 for all images were performed. [123I]FP-CIT-SPECT was reported pathologic with reductions of striatal DAT binding bilaterally (arrow in Figure 1A) and low contrast between striatal and cortical binding (arrowheads in Figure 1A). The specific binding ratio was calculated using occipital region as a reference (18), and the standard deviations from the reference value mean (Z-score) were calculated using BRASS HERMES software containing age-corrected control population: left caudate nucleus 1.77 (Z-Score −4.2), right caudate 1.81 (Z-Score −3.91), left putamen 1.68 (Z-Score −3.65), and right putamen 1.54 (Z-Score −4.08).
Figure 1 Representative [123I]FP-CIT-SPECT images of the patient. Note inhomogeneous and reduced dopamine transporter binding of the radiopharmaceutical in putamen bilaterally (arrow in A) and low contrast between striatal and cortical binding during short-term bupropion therapy (arrowheads in A), which normalized after a wash-out phase of four half-life periods (arrow and arrowheads in B). Bupropion reduced the binding of [123I]FP-CIT up to 45% (i.e., in right putamen).
Subsequently, consultant neurologist was involved revealing general slowness of movements without true bradykinesia with bilateral reduction of arm pendular movement upon walking. Rigidity was not detected, but active resistance. Importantly, the ongoing therapy with bupropion was noted, whereby the serum blood levels of bupropion (43 ng/ml) and the active metabolite hydroxybupropion (2,332 ng/ml) measured on the day of the neurologic examination were within the therapeutic range. Once the repetition of [123I]FP-CIT SPECT after a wash-out phase was suggested, bupropion was discontinued for 8 days (half-life period 20–37 h). At the day of [123I]FP-CIT-SPECT rescan, the serum blood level for bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml. [123I]FP-CIT SPECT was reported normal (Figure 1B) using the same analysis, with overall normalization of specific binding ratios and Z-scores: left caudate nucleus 3.18 (Z-score −0.2), right caudate nucleus 3.28 (Z-score −0.63), left putamen 3.08 (Z-score −0.51) and right putamen 2.94 (Z-score −0.05).
In the course of the comprehensive differential diagnostics, laboratory tests including blood, urine and cerebrospinal fluid, electroencephalography, and [18F]-FDG PET/CT were performed revealing largely unremarkable results. After degenerative parkinsonism, dementia, autoimmune encephalitis, and other degenerative and inflammatory processes could be excluded, further therapeutic optimization was undertaken. While the antidepressant treatment with venlafaxine and vortioxetine was discontinued, tranylcypromine was initiated after the necessary wash-out phase. While staying on a low-tyramine diet, tranylcypromine was well-tolerated by the patient who partially responded to this treatment adaptation. Subsequently, tranylcypromine was slowly increased up to 50 mg/die. Moreover, the patient received clozapine as additional augmentation treatment that was gradually optimized up to 100 mg/die. Under a treatment regimen including tranylcypromine 50 mg, mirtazapine 30 mg, clozapine 100 mg, aripiprazole 10 mg, and clonazepam 2 mg/die that was accompanied by regular psychotherapeutic-, physiotherapeutic and ergotherapeutic support, a remarkable reduction of her depressive and psychotic symptoms was achieved. The adherent patient showed a total score of 28 at the MADRS and of four at the CGI-S and could be discharged from psychiatric inpatient care. Continuing the abovementioned psychopharmacotherapy she was subsequently treated as outpatient and received psychosocial support at home.
Discussion
The present case report could show effect of blood serum levels of bupropion and its active metabolite hydroxybupropion on [123I]FP-CIT binding to DAT. Hereby, therapeutic doses of bupropion reduced the binding of [123I]FP-CIT ~45–50% throughout the striatum, that was reversible after four half-life periods of bupropion. Since there was no further change in the ongoing therapy, in particular concerning venlafaxine and vortioxetine or mirtazapine, we attribute the observed effect to bupropion. Bupropion is a dose-dependent norepinephrine-dopamine reuptake inhibitor (19), with high occupancy at higher doses. Previous studies suggested changed DAT binding properties in depressed individuals. However, it is still a matter of debate, whether the primary mechanism is down-regulation (19) or up-regulation of DAT (20). Thus, concomitant therapy with bupropion may lead to a significant loss of [123I]FP-CIT binding and hence, might result in false positive diagnosis of degenerative parkinsonism. The [123I]FP-CIT binding pattern in our patient, however, appeared atypical for idiopathic PD and DLB (21), showing a reduced DAT binding throughout the striatum. Indeed, a recent paper noted similar observation, although some asymmetry in [123I]FP-CIT binding in a patient under bupropion therapy was reported (22). Thus, careful visual examination of DAT scan in a patient under dopaminergic medications, such as bupropion, may be critical (5). Taken together, our data suggest, that a discontinuation of bupropion of at least four half-life periods is necessary prior to [123I]FP-CIT scan. However, further prospective studies are needed to examine whether longer discontinuation is necessary, as suggested by some authors (22). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with DAT. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to DAT imaging. This might be of crucial importance especially in patients suffering from late onset depression that was recently related to elevated rates of motor and non-motor symptoms known from degenerative parkinsonian syndromes as well as to altered [123I]FP-CIT binding and, hence, to increased risk of PD and DLB (8).
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
IM and LB were responsible for clinical care and data analysis and drafted the manuscript. KP, DW, and SK supervised clinical care and critically revised the manuscript. TT-W critically revised the manuscript and performed and analyzed [123I]FP-CIT-SPECT scans. All authors contributed to the article and approved the submitted version.
Conflict of Interest
IM received grant from Takeda. LB received travel grants and consultant/speaker honoraria from AOP Orphan, Medizin Medien Austria, Vertretungsnetz, Schwabe Austria, Janssen, and Angelini. KP received honoraria from AOP Orphan Pharmaceuticals, Germania Pharmaceuticals, Lundbeck, and Janssen-Cilag. SK received grants/research support, consulting fees, and/or honoraria from Angelini, AOP Orphan Pharmaceuticals, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. DW received lecture fees/authorship honoraria from Angelini, Lundbeck, and Medizin Medien Austria. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 375 mg (milligrams). | DrugDosage | CC BY | 33692710 | 19,261,348 | 2021 |
What was the outcome of reaction 'Drug interaction'? | Case Report: Bupropion Reduces the [123I]FP-CIT Binding to Striatal Dopamine Transporter.
The diagnosis of parkinsonian syndromes in patients with severe depression may be challenging due to overlapping clinical phenomena, especially regarding psychomotor and affective symptoms. [123I]FP-CIT-SPECT is a useful method to detect degenerative parkinsonian disorders. However, some drugs may influence the tracer binding and thus alter the result. We present a case of 56-year-old female inpatient with difficult-to-treat late-onset depression. Since the current major depressive episode (MDE) was accompanied by psychotic features including delusions and hallucinations as well as hypokinesia, stooped posture and hypomimia, underlying degenerative parkinsonism was suspected. The pathologic [123I]FP-CIT-SPECT scan under ongoing antidepressant therapy with bupropion 300 mg/die (serum level of bupropion 43 ng/ml and hydroxybupropion 2,332 ng/ml) showed reduced [123I]FP-CIT binding throughout the striatum. The scan normalized upon a wash-out phase of four half-time periods (serum level of bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with the dopamine transporter. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to dopamine transporter imaging.
Introduction
The diagnosis of parkinsonian syndromes in patients suffering from severe depression can be challenging. On one hand, these patients may exhibit hypomimia-like facial expression, parkinsonian-like posture or develop psychotic features (1). On the other hand, depression as the most common non-motor symptom in Parkinson's disease (PD) precedes the motor symptoms for ~10 years (2). In doubtful cases, [123I]FP-CIT-SPECT is a useful tool to detect decrease in striatal binding to dopamine transporters (DAT) (3) due to loss of nigrostriatal terminals (4). However, commonly prescribed psychopharmacotherapeutics that bind to DAT may change the binding properties of the tracer (5) and hence, alter the results (6). Although several drugs have been identified, occasionally patients and physicians are not aware that these drugs ought to be paused prior to [123I]FP-CIT-SPECT imaging. This results either in prolonging the diagnostic procedures or, if not considered by specialists, even in imprecise diagnosis. Here we report on a prominent effect of short-term bupropion therapy on [123I]FP-CIT-SPECT imaging.
Case Presentation
The 56-year-old female inpatient (weight: 70 kg, height: 160 cm) had almost a 1-year history of a difficult-to-treat depression (7) with late onset (8). In the course of the current severe major depressive episode (MDE) with psychotic symptoms (International Classification of Diseases, 10th revision, ICD-10 (9): F32.3) that represented her first MDE so far, the patient was anhedonic and exhibited indecisiveness, feelings of hopelessness and worthlessness as well as excessive guilt and diminished ability to concentrate. In the course of her subjective cognitive decline, the patient exhibited a total score of 28/30 at the Mini-Mental State Examination (MMSE) (10) and of 15/18 at the DemTect (11) representing values within the normal range. Furthermore, she suffered from psychomotor slowing, loss of interest and pleasure affecting her hobbies and nearly all activities including the necessary daily routine, as well as delusions and hallucinations. She negated suicidal ideation and there was no suicidal history. The patient showed a total score of 46 at the Montgomery-Åsberg Depression Rating Scale (MADRS) (12) and 6 at the Clinical Global Impressions Scale (CGI-S) (13). In terms of psychiatric and somatic comorbidities, the patient suffered from nicotine dependence (ICD-10: F17.2) and psoriasis vulgaris (ICD-10: L40.0).
The antidepressant combination treatment with mirtazapine 45 mg and venlafaxine 375 mg was expanded with vortioxetine 10 mg/die, but failed to improve the symptoms. Neither augmentation with second-generation antipsychotics (aripiprazole 20 mg/die) (14) and S-ketamine (15) that was administered 2–3 times/week intravenously (up to 50 mg per infusion), nor a series of 11 electroconvulsive therapies (ECT) with subsequent regular maintenance ECTs, all with bilateral stimulation up to 100%, improved the severe depressive symptoms (16).
Due to massive anhedonia, progressive hypomimia, general slowness of movements, delusions and hallucinations, a suspicion of degenerative parkinsonism was raised. Since there were no postural instability and no history of falls, dementia with Lewy bodies (DLB) was considered as a differential diagnosis. While the cranial magnetic resonance imaging was unremarkable, [123I]FP-CIT-SPECT was initiated. Four days prior to the [123I]FP-CIT-SPECT examination the antidepressant treatment was adapted adding bupropion 150 mg/die that was increased to 300 mg/die on the day of [123I]FP-CIT-SPECT. An intravenous bolus injection of ~185 MBq [123I]FP-CIT according to GMP criteria was applied ~1 h after the medication intake and ~3 h before the acquisition of the scans. A three-headed Gamma camera (IRIX 465, Philips Medical System) system was used for SPECT Imaging (3° steps/360°, 60 s per step, 40 frames, pixel size of 3,50 mm, pixel matrix of 128 × 128, LEHR-PAR collimator). OSEM reconstruction (5 subsets, 16 iterations), post-filtering with 3 D Gauss filter (FWHM 7 cm) and Chang's attenuation correction (17) with an attenuation coefficient of 0.15 for all images were performed. [123I]FP-CIT-SPECT was reported pathologic with reductions of striatal DAT binding bilaterally (arrow in Figure 1A) and low contrast between striatal and cortical binding (arrowheads in Figure 1A). The specific binding ratio was calculated using occipital region as a reference (18), and the standard deviations from the reference value mean (Z-score) were calculated using BRASS HERMES software containing age-corrected control population: left caudate nucleus 1.77 (Z-Score −4.2), right caudate 1.81 (Z-Score −3.91), left putamen 1.68 (Z-Score −3.65), and right putamen 1.54 (Z-Score −4.08).
Figure 1 Representative [123I]FP-CIT-SPECT images of the patient. Note inhomogeneous and reduced dopamine transporter binding of the radiopharmaceutical in putamen bilaterally (arrow in A) and low contrast between striatal and cortical binding during short-term bupropion therapy (arrowheads in A), which normalized after a wash-out phase of four half-life periods (arrow and arrowheads in B). Bupropion reduced the binding of [123I]FP-CIT up to 45% (i.e., in right putamen).
Subsequently, consultant neurologist was involved revealing general slowness of movements without true bradykinesia with bilateral reduction of arm pendular movement upon walking. Rigidity was not detected, but active resistance. Importantly, the ongoing therapy with bupropion was noted, whereby the serum blood levels of bupropion (43 ng/ml) and the active metabolite hydroxybupropion (2,332 ng/ml) measured on the day of the neurologic examination were within the therapeutic range. Once the repetition of [123I]FP-CIT SPECT after a wash-out phase was suggested, bupropion was discontinued for 8 days (half-life period 20–37 h). At the day of [123I]FP-CIT-SPECT rescan, the serum blood level for bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml. [123I]FP-CIT SPECT was reported normal (Figure 1B) using the same analysis, with overall normalization of specific binding ratios and Z-scores: left caudate nucleus 3.18 (Z-score −0.2), right caudate nucleus 3.28 (Z-score −0.63), left putamen 3.08 (Z-score −0.51) and right putamen 2.94 (Z-score −0.05).
In the course of the comprehensive differential diagnostics, laboratory tests including blood, urine and cerebrospinal fluid, electroencephalography, and [18F]-FDG PET/CT were performed revealing largely unremarkable results. After degenerative parkinsonism, dementia, autoimmune encephalitis, and other degenerative and inflammatory processes could be excluded, further therapeutic optimization was undertaken. While the antidepressant treatment with venlafaxine and vortioxetine was discontinued, tranylcypromine was initiated after the necessary wash-out phase. While staying on a low-tyramine diet, tranylcypromine was well-tolerated by the patient who partially responded to this treatment adaptation. Subsequently, tranylcypromine was slowly increased up to 50 mg/die. Moreover, the patient received clozapine as additional augmentation treatment that was gradually optimized up to 100 mg/die. Under a treatment regimen including tranylcypromine 50 mg, mirtazapine 30 mg, clozapine 100 mg, aripiprazole 10 mg, and clonazepam 2 mg/die that was accompanied by regular psychotherapeutic-, physiotherapeutic and ergotherapeutic support, a remarkable reduction of her depressive and psychotic symptoms was achieved. The adherent patient showed a total score of 28 at the MADRS and of four at the CGI-S and could be discharged from psychiatric inpatient care. Continuing the abovementioned psychopharmacotherapy she was subsequently treated as outpatient and received psychosocial support at home.
Discussion
The present case report could show effect of blood serum levels of bupropion and its active metabolite hydroxybupropion on [123I]FP-CIT binding to DAT. Hereby, therapeutic doses of bupropion reduced the binding of [123I]FP-CIT ~45–50% throughout the striatum, that was reversible after four half-life periods of bupropion. Since there was no further change in the ongoing therapy, in particular concerning venlafaxine and vortioxetine or mirtazapine, we attribute the observed effect to bupropion. Bupropion is a dose-dependent norepinephrine-dopamine reuptake inhibitor (19), with high occupancy at higher doses. Previous studies suggested changed DAT binding properties in depressed individuals. However, it is still a matter of debate, whether the primary mechanism is down-regulation (19) or up-regulation of DAT (20). Thus, concomitant therapy with bupropion may lead to a significant loss of [123I]FP-CIT binding and hence, might result in false positive diagnosis of degenerative parkinsonism. The [123I]FP-CIT binding pattern in our patient, however, appeared atypical for idiopathic PD and DLB (21), showing a reduced DAT binding throughout the striatum. Indeed, a recent paper noted similar observation, although some asymmetry in [123I]FP-CIT binding in a patient under bupropion therapy was reported (22). Thus, careful visual examination of DAT scan in a patient under dopaminergic medications, such as bupropion, may be critical (5). Taken together, our data suggest, that a discontinuation of bupropion of at least four half-life periods is necessary prior to [123I]FP-CIT scan. However, further prospective studies are needed to examine whether longer discontinuation is necessary, as suggested by some authors (22). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with DAT. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to DAT imaging. This might be of crucial importance especially in patients suffering from late onset depression that was recently related to elevated rates of motor and non-motor symptoms known from degenerative parkinsonian syndromes as well as to altered [123I]FP-CIT binding and, hence, to increased risk of PD and DLB (8).
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
IM and LB were responsible for clinical care and data analysis and drafted the manuscript. KP, DW, and SK supervised clinical care and critically revised the manuscript. TT-W critically revised the manuscript and performed and analyzed [123I]FP-CIT-SPECT scans. All authors contributed to the article and approved the submitted version.
Conflict of Interest
IM received grant from Takeda. LB received travel grants and consultant/speaker honoraria from AOP Orphan, Medizin Medien Austria, Vertretungsnetz, Schwabe Austria, Janssen, and Angelini. KP received honoraria from AOP Orphan Pharmaceuticals, Germania Pharmaceuticals, Lundbeck, and Janssen-Cilag. SK received grants/research support, consulting fees, and/or honoraria from Angelini, AOP Orphan Pharmaceuticals, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. DW received lecture fees/authorship honoraria from Angelini, Lundbeck, and Medizin Medien Austria. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered | ReactionOutcome | CC BY | 33692710 | 19,253,442 | 2021 |
What was the outcome of reaction 'False positive investigation result'? | Case Report: Bupropion Reduces the [123I]FP-CIT Binding to Striatal Dopamine Transporter.
The diagnosis of parkinsonian syndromes in patients with severe depression may be challenging due to overlapping clinical phenomena, especially regarding psychomotor and affective symptoms. [123I]FP-CIT-SPECT is a useful method to detect degenerative parkinsonian disorders. However, some drugs may influence the tracer binding and thus alter the result. We present a case of 56-year-old female inpatient with difficult-to-treat late-onset depression. Since the current major depressive episode (MDE) was accompanied by psychotic features including delusions and hallucinations as well as hypokinesia, stooped posture and hypomimia, underlying degenerative parkinsonism was suspected. The pathologic [123I]FP-CIT-SPECT scan under ongoing antidepressant therapy with bupropion 300 mg/die (serum level of bupropion 43 ng/ml and hydroxybupropion 2,332 ng/ml) showed reduced [123I]FP-CIT binding throughout the striatum. The scan normalized upon a wash-out phase of four half-time periods (serum level of bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with the dopamine transporter. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to dopamine transporter imaging.
Introduction
The diagnosis of parkinsonian syndromes in patients suffering from severe depression can be challenging. On one hand, these patients may exhibit hypomimia-like facial expression, parkinsonian-like posture or develop psychotic features (1). On the other hand, depression as the most common non-motor symptom in Parkinson's disease (PD) precedes the motor symptoms for ~10 years (2). In doubtful cases, [123I]FP-CIT-SPECT is a useful tool to detect decrease in striatal binding to dopamine transporters (DAT) (3) due to loss of nigrostriatal terminals (4). However, commonly prescribed psychopharmacotherapeutics that bind to DAT may change the binding properties of the tracer (5) and hence, alter the results (6). Although several drugs have been identified, occasionally patients and physicians are not aware that these drugs ought to be paused prior to [123I]FP-CIT-SPECT imaging. This results either in prolonging the diagnostic procedures or, if not considered by specialists, even in imprecise diagnosis. Here we report on a prominent effect of short-term bupropion therapy on [123I]FP-CIT-SPECT imaging.
Case Presentation
The 56-year-old female inpatient (weight: 70 kg, height: 160 cm) had almost a 1-year history of a difficult-to-treat depression (7) with late onset (8). In the course of the current severe major depressive episode (MDE) with psychotic symptoms (International Classification of Diseases, 10th revision, ICD-10 (9): F32.3) that represented her first MDE so far, the patient was anhedonic and exhibited indecisiveness, feelings of hopelessness and worthlessness as well as excessive guilt and diminished ability to concentrate. In the course of her subjective cognitive decline, the patient exhibited a total score of 28/30 at the Mini-Mental State Examination (MMSE) (10) and of 15/18 at the DemTect (11) representing values within the normal range. Furthermore, she suffered from psychomotor slowing, loss of interest and pleasure affecting her hobbies and nearly all activities including the necessary daily routine, as well as delusions and hallucinations. She negated suicidal ideation and there was no suicidal history. The patient showed a total score of 46 at the Montgomery-Åsberg Depression Rating Scale (MADRS) (12) and 6 at the Clinical Global Impressions Scale (CGI-S) (13). In terms of psychiatric and somatic comorbidities, the patient suffered from nicotine dependence (ICD-10: F17.2) and psoriasis vulgaris (ICD-10: L40.0).
The antidepressant combination treatment with mirtazapine 45 mg and venlafaxine 375 mg was expanded with vortioxetine 10 mg/die, but failed to improve the symptoms. Neither augmentation with second-generation antipsychotics (aripiprazole 20 mg/die) (14) and S-ketamine (15) that was administered 2–3 times/week intravenously (up to 50 mg per infusion), nor a series of 11 electroconvulsive therapies (ECT) with subsequent regular maintenance ECTs, all with bilateral stimulation up to 100%, improved the severe depressive symptoms (16).
Due to massive anhedonia, progressive hypomimia, general slowness of movements, delusions and hallucinations, a suspicion of degenerative parkinsonism was raised. Since there were no postural instability and no history of falls, dementia with Lewy bodies (DLB) was considered as a differential diagnosis. While the cranial magnetic resonance imaging was unremarkable, [123I]FP-CIT-SPECT was initiated. Four days prior to the [123I]FP-CIT-SPECT examination the antidepressant treatment was adapted adding bupropion 150 mg/die that was increased to 300 mg/die on the day of [123I]FP-CIT-SPECT. An intravenous bolus injection of ~185 MBq [123I]FP-CIT according to GMP criteria was applied ~1 h after the medication intake and ~3 h before the acquisition of the scans. A three-headed Gamma camera (IRIX 465, Philips Medical System) system was used for SPECT Imaging (3° steps/360°, 60 s per step, 40 frames, pixel size of 3,50 mm, pixel matrix of 128 × 128, LEHR-PAR collimator). OSEM reconstruction (5 subsets, 16 iterations), post-filtering with 3 D Gauss filter (FWHM 7 cm) and Chang's attenuation correction (17) with an attenuation coefficient of 0.15 for all images were performed. [123I]FP-CIT-SPECT was reported pathologic with reductions of striatal DAT binding bilaterally (arrow in Figure 1A) and low contrast between striatal and cortical binding (arrowheads in Figure 1A). The specific binding ratio was calculated using occipital region as a reference (18), and the standard deviations from the reference value mean (Z-score) were calculated using BRASS HERMES software containing age-corrected control population: left caudate nucleus 1.77 (Z-Score −4.2), right caudate 1.81 (Z-Score −3.91), left putamen 1.68 (Z-Score −3.65), and right putamen 1.54 (Z-Score −4.08).
Figure 1 Representative [123I]FP-CIT-SPECT images of the patient. Note inhomogeneous and reduced dopamine transporter binding of the radiopharmaceutical in putamen bilaterally (arrow in A) and low contrast between striatal and cortical binding during short-term bupropion therapy (arrowheads in A), which normalized after a wash-out phase of four half-life periods (arrow and arrowheads in B). Bupropion reduced the binding of [123I]FP-CIT up to 45% (i.e., in right putamen).
Subsequently, consultant neurologist was involved revealing general slowness of movements without true bradykinesia with bilateral reduction of arm pendular movement upon walking. Rigidity was not detected, but active resistance. Importantly, the ongoing therapy with bupropion was noted, whereby the serum blood levels of bupropion (43 ng/ml) and the active metabolite hydroxybupropion (2,332 ng/ml) measured on the day of the neurologic examination were within the therapeutic range. Once the repetition of [123I]FP-CIT SPECT after a wash-out phase was suggested, bupropion was discontinued for 8 days (half-life period 20–37 h). At the day of [123I]FP-CIT-SPECT rescan, the serum blood level for bupropion was 0.4 ng/ml and for hydroxybupropion 80.5 ng/ml. [123I]FP-CIT SPECT was reported normal (Figure 1B) using the same analysis, with overall normalization of specific binding ratios and Z-scores: left caudate nucleus 3.18 (Z-score −0.2), right caudate nucleus 3.28 (Z-score −0.63), left putamen 3.08 (Z-score −0.51) and right putamen 2.94 (Z-score −0.05).
In the course of the comprehensive differential diagnostics, laboratory tests including blood, urine and cerebrospinal fluid, electroencephalography, and [18F]-FDG PET/CT were performed revealing largely unremarkable results. After degenerative parkinsonism, dementia, autoimmune encephalitis, and other degenerative and inflammatory processes could be excluded, further therapeutic optimization was undertaken. While the antidepressant treatment with venlafaxine and vortioxetine was discontinued, tranylcypromine was initiated after the necessary wash-out phase. While staying on a low-tyramine diet, tranylcypromine was well-tolerated by the patient who partially responded to this treatment adaptation. Subsequently, tranylcypromine was slowly increased up to 50 mg/die. Moreover, the patient received clozapine as additional augmentation treatment that was gradually optimized up to 100 mg/die. Under a treatment regimen including tranylcypromine 50 mg, mirtazapine 30 mg, clozapine 100 mg, aripiprazole 10 mg, and clonazepam 2 mg/die that was accompanied by regular psychotherapeutic-, physiotherapeutic and ergotherapeutic support, a remarkable reduction of her depressive and psychotic symptoms was achieved. The adherent patient showed a total score of 28 at the MADRS and of four at the CGI-S and could be discharged from psychiatric inpatient care. Continuing the abovementioned psychopharmacotherapy she was subsequently treated as outpatient and received psychosocial support at home.
Discussion
The present case report could show effect of blood serum levels of bupropion and its active metabolite hydroxybupropion on [123I]FP-CIT binding to DAT. Hereby, therapeutic doses of bupropion reduced the binding of [123I]FP-CIT ~45–50% throughout the striatum, that was reversible after four half-life periods of bupropion. Since there was no further change in the ongoing therapy, in particular concerning venlafaxine and vortioxetine or mirtazapine, we attribute the observed effect to bupropion. Bupropion is a dose-dependent norepinephrine-dopamine reuptake inhibitor (19), with high occupancy at higher doses. Previous studies suggested changed DAT binding properties in depressed individuals. However, it is still a matter of debate, whether the primary mechanism is down-regulation (19) or up-regulation of DAT (20). Thus, concomitant therapy with bupropion may lead to a significant loss of [123I]FP-CIT binding and hence, might result in false positive diagnosis of degenerative parkinsonism. The [123I]FP-CIT binding pattern in our patient, however, appeared atypical for idiopathic PD and DLB (21), showing a reduced DAT binding throughout the striatum. Indeed, a recent paper noted similar observation, although some asymmetry in [123I]FP-CIT binding in a patient under bupropion therapy was reported (22). Thus, careful visual examination of DAT scan in a patient under dopaminergic medications, such as bupropion, may be critical (5). Taken together, our data suggest, that a discontinuation of bupropion of at least four half-life periods is necessary prior to [123I]FP-CIT scan. However, further prospective studies are needed to examine whether longer discontinuation is necessary, as suggested by some authors (22). Our report should serve as a cautionary note for use of [123I]FP-CIT in depressed patients, particularly in those treated with drugs interfering with DAT. Furthermore, our case argues for a need of consultation of a movement disorder specialist prior to DAT imaging. This might be of crucial importance especially in patients suffering from late onset depression that was recently related to elevated rates of motor and non-motor symptoms known from degenerative parkinsonian syndromes as well as to altered [123I]FP-CIT binding and, hence, to increased risk of PD and DLB (8).
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Ethics Statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
IM and LB were responsible for clinical care and data analysis and drafted the manuscript. KP, DW, and SK supervised clinical care and critically revised the manuscript. TT-W critically revised the manuscript and performed and analyzed [123I]FP-CIT-SPECT scans. All authors contributed to the article and approved the submitted version.
Conflict of Interest
IM received grant from Takeda. LB received travel grants and consultant/speaker honoraria from AOP Orphan, Medizin Medien Austria, Vertretungsnetz, Schwabe Austria, Janssen, and Angelini. KP received honoraria from AOP Orphan Pharmaceuticals, Germania Pharmaceuticals, Lundbeck, and Janssen-Cilag. SK received grants/research support, consulting fees, and/or honoraria from Angelini, AOP Orphan Pharmaceuticals, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. DW received lecture fees/authorship honoraria from Angelini, Lundbeck, and Medizin Medien Austria. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered | ReactionOutcome | CC BY | 33692710 | 19,261,348 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dermatitis atopic'. | Case Report: A Case of Acute Cellular Rejection Due to Atopic Dermatitis Exacerbation 3 Years After Heart Transplantation.
Little evidence has been presented about the association between previous atopic/allergic disease and graft rejection after solid organ transplantation. Thus, we present a case wherein acute cellular rejection (ACR) after heart transplantation (HTx) was noted along with exacerbation of atopic disease.
A 32-year-old man was admitted at our hospital for regular monitoring of graft rejection. He had undergone heart transplant 3 years prior due to dilated cardiomyopathy. Echocardiogram revealed good biventricular function, and no abnormal findings were found in blood sampling tests. However, biopsy showed moderate ACR [Grade 2R(ISHLT 2004)/3A(ISHLT 1990)], which required twice-repeated steroid pulses with intensified immunosuppression. Meanwhile, his atopic dermatitis, which was diagnosed before having heart failure, was getting worse for the past 6 months. The exacerbation of atopic dermatitis was presumed to be related to the development of the intractable cellular rejection.
This case suggested the association of atopic disease and graft rejection after HTx. We examined 76 patients from a cohort of previous studies who underwent HTx at our hospital, which suggested that patients with atopic/allergic disorders such as atopic dermatitis and asthma tended to have a significantly higher frequency of moderate rejection than non-allergic patients. (p = 0.012; Fisher's exact test). Our case also suggests that exacerbation of atopic dermatitis might cause graft rejection of the transplanted organ, so that it is important to carefully evaluate the risk of graft rejection if there is a previous history of atopic/allergic disease.
Introduction
Heart transplantation (HTx) is a radical treatment that saves the lives of those with end-stage heart failure. Although the surgical procedures and perioperative management methods have been established, control of acute and chronic rejection and the harmful effects of immunosuppressants remain as the biggest challenges. Previous studies have reported that through the response of the T-cells, the frequency of graft rejection increases in the presence of atopic/allergic diseases (1, 2). The pathophysiology of many atopic/allergic diseases is associated with a type 2 T helpler cell (Th2)-based inflammatory response that involves the production of cytokines such as interleukin (IL)-4, IL-5, and IL-13 (3). The untoward effect of Th2-based inflammation and cytokines is presumed to increase graft rejection by making CD4+ effector T-cells resistant to regulatory T-cells (Tregs) (4). Several studies have also reported the critical role Tregs play in immune tolerance and immunosuppression (5, 6). In this report, we present a case of graft rejection reaction that correlated with aggravation of atopic dermatitis 3 years after HTx.
Case Description
We present the case of a 32-year-old man who underwent orthotropic HTx at our hospital due to dilated cardiomyopathy (DCM). The patient was diagnosed with atopic dermatitis during childhood which necessitated the use of topical drugs. At 24 years old, he noted dyspnea on exertion. Shortly after, he was diagnosed with DCM and subsequently developed severe drug-resistant heart failure. At 25 years old, a left ventricular assist device was implanted as bridge therapy for heart failure. At 29 years old, orthotropic HTx was performed at our hospital. The patient was treated with standard immunosuppression therapy consisting of cyclosporine, mycophenolate mofetil (MMF), and prednisolone. We performed endomyocardial biopsy according to our institutional protocol, which consists of examinations at the 1st, 2nd, 3rd, 4th, 6th, 8th, 10th, 12th, 18th, and 24th post-procedural weeks and the 1st, and 2nd post-procedural years. During the patient’s follow-ups, there were three events of mild acute cellular rejection (ACR) (grade 1R ISHLT2004/grade 2 ISHLT 1990) within two years, whereas in all other examinations there were no findings of ACR. In addition, anti-HLA antibodies were not detected during any of the follow-ups. There were also no signs of heart failure such as dyspnea and edema, and the immunosuppressive treatment course was stable. The dose of prednisolone was gradually reduced according to the policy of our institution and it was turned off about one year after HTx. After 3 years, the patient was hospitalized to undergo a regular endomyocardial biopsy (EMB). On admission, his vital signs were normal, with no leg edema and no jugular dilation. Of note is that his atopic dermatitis worsened from the previous winter season and six months before hospitalization. This was evidenced by erythema and scaling on the neck, precordium, and back, and erythema with scabs and exudate were found on the arms and legs. A blood test on admission revealed mild anemia. The blood counts of the other two strains were within the normal range, and the eosinophil count was normal. Liver and kidney function tests were normal. Chest X-ray showed normal heart shadow and no pleural effusion. Electrocardiogram (ECG) revealed sinus rhythm of 73 bpm with no ST-T changes. Transthoracic echocardiography showed normal left and right ventricular function, and left ventricle ejection fraction was estimated at 73% (Teichholz). Echocardiography parameters of intraventricular and posterior left ventricle wall diameters were 6 and 8 mm, respectively. The immunosuppressive drugs taken by the patient at the time of hospitalization were MMF 1,750 mg/day and cyclosporine 150 mg/day. Cyclosporine serum level (the trough value) was 145 ng/ml, which was within the optimum range. Right heart catheterization showed that the mean right atrial pressure, mean pulmonary artery wedge pressure, mean pulmonary artery pressure, and cardiac index (Fick) were 5, 11, 16 mmHg, and 3.63 L/min/m2, respectively, suggesting that intracardiac pressure was within the normal range and cardiac output was maintained. Coronary artery angiography showed no significant stenosis in the coronary arteries. On the other hand, EMB showed infiltration of multiple inflammatory cells with myocardial damage, which corresponded ACR with grade 2R (ISHLT 2004)/grade (3A ISHLT 1990) (Figure 1). To counteract the graft rejection, he was treated with a 3-day course of parenteral methylprednisolone (1,000 mg/day) and then oral prednisolone 25 mg/day, which was gradually reduced every two days. In addition, the dose of cyclosporine was increased from 150 mg/day to 160 mg/day. However, repeat EMB after 1 week also revealed similar findings of ACR with a grade of 2R (ISHLT 2004)/3A (ISHLT 1990). The patient was given steroid pulse therapy for 3 days, and MMF was shifted to everolimus 1 mg/day to intensify immunosuppression. Repeat EMB after 1 week showed the improvement of graft rejection (Grade 0). He was discharged without any overt complications. In addition, atopic dermatitis also improved by intensifying immunosuppressive drugs with topical drugs. During subsequent follow-ups, no adverse or clinical events were observed. One year after, 4 years after HTx, significant ACR was not noted [grade 1R (ISHLT 2004)/1A (ISHLT 1990)] and there was no exacerbation of atopic dermatitis.
Figure 1 Hematoxylin and eosin stain of endocardial biopsy sample featuring myocyte injury with multiple lymphocytic infiltration. [Grade2R(ISHLT 2004)/3A(ISHLT 1990)]. (A) First endocardial biopsy (B) Second endocardial biopsy.
Discussion
Previous studies have reported cases in which concomitant atopic/allergic disorders had an increased incidence of graft rejection. Previous investigations using mice have demonstrated that classic allergic disease such as airway hyperresponsiveness and allergic conjunctivitis, exacerbates corneal allograft rejection (1, 4). Nguyen et al. have indicated that the frequency of corneal graft rejection following normal-risk keratoplasty was significantly increased in patients with atopic dermatitis (2). Seung et al. have shown that acute rejection after renal transplantation is more common and severe in patients with atopy (7). However, no case reports exist about the association of atopic/allergic disease and graft rejection after HTx, and in our knowledge, this is the first report of its kind.
Several hypotheses have been proposed to explain the association between atopic/allergic disease and graft rejection. Atopic dermatitis and allergic airway inflammation are Th2-dominant allergic diseases. Th2 produces cytokines such as IL-4, which induces immunoglobulin E (IgE) production by acting on B-cells, while mast cells release cytokines such as IL-6 and tumor growth factor-beta (TGF-β) in response to the involvement of the IgE receptor (FcϵRI) complex on the cell surface (3, 8). The cytokines induced by Th2 are reported to suppress the effect of Tregs, leading to the enhancement of CD4+ effector T-cells. In studies with mice, it has been reported that IL-4 exacerbates corneal allograft rejection by making CD4+ effector T-cells resistant to Tregs (9). Tregs have been reported to play important roles in the suppression of graft rejection following organ transplant (3). From these findings, there is a possibility that the risk of rejection may increase via such T-cell responses in patients with atopic/allergic diseases. On the other hand, several reports have described the association between eosinophil and graft rejection after heart and lung transplantation (10–12). Acute graft rejection was reported to be associated with the local productions of IL-4 and IL-5 together with eosinophil infiltration (10). Several studies have reported on the impact of eosinophil on the development of graft rejection (11, 12). Eosinophil was reported to correlate with the severity of atopic dermatitis (13), and thus, might add some hints for the explanation of the association between atopy and graft rejection. However, the present case did not represent eosinophilia, so the correct explanation of the association between atopic dermatitis and graft rejection in this case had not been clarified.
For further validation of the association between previous history of atopic/allergic disease and the risk of ACR, we examined 76 patients from a cohort of previous study who underwent heart transplantation at our hospital between August 2007 and May 2017 (14). Six patients (7.9%) had a history of atopic/allergic diseases such as bronchial asthma (n = 4) and atopic dermatitis (n = 3), one patient had both atopic dermatitis and bronchial asthma (Table 1). The basic characteristics are presented in Table 1. The percentage of atopic/allergic disease was slightly low possibly owing to the selection of candidates for HTx. During the chronic phase after HTx (1–3 years), patients with atopic/allergic disease tended to have a significantly higher frequency of moderate rejection [(Grade 2R (ISHLT 2004)/3A (ISHLT 1990) or higher)] than patients without atopic/allergic disease [(p = 0.012; Fisher’s exact test), Odds ratio (95% CI) 10.73 (1.75 to 65.90)] (Figure 2). On the other hand, there was no significant difference in the frequency of moderate rejection [p = 0.40, odds ratio (95% CI) 2.67 (0.46 to 15.53)] less than 1 year after HTx. Based on the above, the risk of graft rejection, especially during the chronic phase, increases in atopic/allergic diseases. The survival curve was not significantly different between these two groups (Figure 3).
Table 1 Basic characteristics.
All With allergic disease Without allergic disease P value
(n = 76) (n = 6) (n = 70)
Age, years 40 (29–53) 44.5 (27.5–53.0) 39.5 (28.8–53.2) 0.80
Male 53 (69.7) 6 (100) 47 (67.1) 0.09
BMI, kg/m2 20.0 (17.1–23.1) 23.8 (20.9–27.2) 19.8 (17.4–23.1) 0.0075
WBC, μl 5,600 (4,200–6,850) 5,400 (3,950–10,200) 5,600 (4,200–6,750) 0.79
Eosinophils,/μl 11.2 (0–51.7) 17.3 (6.3–61.5) 10.8 (0–51.9) 0.65
Hb, g/dl 11.4 (10.4–12.8) 12.1 (10.9–13.8) 11.4 (10.2–12.8) 0.20
Plt, ×104/μl 21.8 (19.0–24.7) 22.0 (15.9–23.8) 21.8 (19.1–24.8) 0.54
eGFR, 51.6 (39.2–70.1) 45.9 (40.4–62.6) 52.4 (38.9–71.0) 0.59
ml/min/1.73m2
CRP, mg/dl 0.06 (0.02–0.2) 0.035 (0.018–0.18) 0.06 (0.02–0.25) 0.37
BNP, pg/ml 79.2 (44.0–116.5) 64.7 (44.8–88.8) 81.5 (43.7–121.9) 0.45
All variables presented as median (interquartile range) or n (%).
Age was the age at the time of the heart transplantation. Blood test data was data one year after the heart transplantation. P-values were calculated by Fisher’s exact test, t-test or Wilcoxon rank-sum test comparing those with allergic disease and without allergic disease.
BMI, body mass index; WBC, white blood cell; Hb, hemoglobin; Plt, platelet; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein; BNP, B-type natriuretic peptide.
Figure 2 Difference in the development of acute cellular rejection within one year after heart transplantation (HTx) and three years after HTx between patients with and without previous allergic disease. NS, not significant.
Figure 3 Kaplan-Meier survival curve of patients with and without previous allergic disease after heart transplantation. There was no significant difference in survival curves between two groups (Log-rank p = 0.53).
Another lingering question is that despite immunosuppressive therapy, why did the patient develop exacerbation of atopic dermatitis? Both cyclosporin and MMF have been reported to be highly effective for atopic dermatitis. However, some studies have reported paradoxical development of atopic dermatitis after solid organ transplantation (15). Ozdemir et al. demonstrated newly-developed allergies after HTx (16). In addition, some studies have reported the development of allergies after receiving immunosuppressive therapy, but there had been no report about the mechanism of action, which should be elucidated more robustly in the future.
In fact, at our institution, prednisolone is turned off within 1 year after HTx (17). If there is concern about exacerbation of rejection due to exacerbation of atopic/allergic disease as in this case, a regimen such as continuing a small amount of steroid, which will be more effective for atopic/allergic disease, might be better.
Generally speaking, late-onset ACR has been known to have more adverse clinical outcomes as compared to early-onset ACR. However, triggers for late-onset ACR have not been identified. Future studies may focus on finding out the specific causes for late-onset ACR, which can ultimately lead to improvements in the treatment for post-HTx patients.
In a limitation of this study, the chronological association between the graft rejection and the exacerbation of atopic dermatitis in this case was difficult to presume. However, it is more likely that the state of atopic dermatitis affected the state of graft rejection because the impact derived from atopic dermatitis on the systemic immune response might be greater than the impact derived from graft rejection (18). In addition, more concise evaluation of the state of atopic dermatitis might help the correct clarification of the association between atopic dermatitis and graft rejection.
Similar to this case, no reports of graft rejection due to exacerbation of atopic dermatitis have yet to be reported. Patients with a history of allergic disorders such as atopic dermatitis may be at an increased risk of developing immunological rejection after transplantation, requiring a more intensive immunosuppressive regimen and careful follow-up.
Conclusions
ACR following exacerbation of atopic dermatitis 3 years post-HTx is rare and has never been reported. This case highlights the importance of considering all factors that may contribute to graft rejection, regardless of diagnostic findings. However, it is also necessary to determine what processes are involved in this relationship.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by the institutional review board at the University of Tokyo (approval number: 2,650). The patients/participants provided their written informed consent to participate in this study.
Author Contributions
NK: Data collection, statistical analysis, and writing of the manuscript. EA: Conception of the idea, data collection, critical feedback on the manuscript, and writing of the manuscript. CB, MT, JI, MH, KN, KF, and HM: Data collection and critical feedback on the manuscript. MH, MO, and IK: Critical feedback on the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan through Grant-in-Aid 17K09488 (to EA).
Conflict of Interest
EA and MH belong to the Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, University of Tokyo, which is endowed by Actelion Pharmaceuticals Japan Ltd., Otsuka Pharmaceutical, NIPRO CORPORATION, Terumo Corp., Senko Medical Instrument Mfg., Century Medical Inc., Kinetic Concepts Inc., and St. Jude Medical.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISOLONE | DrugsGivenReaction | CC BY | 33692803 | 19,425,894 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Transplant rejection'. | Case Report: A Case of Acute Cellular Rejection Due to Atopic Dermatitis Exacerbation 3 Years After Heart Transplantation.
Little evidence has been presented about the association between previous atopic/allergic disease and graft rejection after solid organ transplantation. Thus, we present a case wherein acute cellular rejection (ACR) after heart transplantation (HTx) was noted along with exacerbation of atopic disease.
A 32-year-old man was admitted at our hospital for regular monitoring of graft rejection. He had undergone heart transplant 3 years prior due to dilated cardiomyopathy. Echocardiogram revealed good biventricular function, and no abnormal findings were found in blood sampling tests. However, biopsy showed moderate ACR [Grade 2R(ISHLT 2004)/3A(ISHLT 1990)], which required twice-repeated steroid pulses with intensified immunosuppression. Meanwhile, his atopic dermatitis, which was diagnosed before having heart failure, was getting worse for the past 6 months. The exacerbation of atopic dermatitis was presumed to be related to the development of the intractable cellular rejection.
This case suggested the association of atopic disease and graft rejection after HTx. We examined 76 patients from a cohort of previous studies who underwent HTx at our hospital, which suggested that patients with atopic/allergic disorders such as atopic dermatitis and asthma tended to have a significantly higher frequency of moderate rejection than non-allergic patients. (p = 0.012; Fisher's exact test). Our case also suggests that exacerbation of atopic dermatitis might cause graft rejection of the transplanted organ, so that it is important to carefully evaluate the risk of graft rejection if there is a previous history of atopic/allergic disease.
Introduction
Heart transplantation (HTx) is a radical treatment that saves the lives of those with end-stage heart failure. Although the surgical procedures and perioperative management methods have been established, control of acute and chronic rejection and the harmful effects of immunosuppressants remain as the biggest challenges. Previous studies have reported that through the response of the T-cells, the frequency of graft rejection increases in the presence of atopic/allergic diseases (1, 2). The pathophysiology of many atopic/allergic diseases is associated with a type 2 T helpler cell (Th2)-based inflammatory response that involves the production of cytokines such as interleukin (IL)-4, IL-5, and IL-13 (3). The untoward effect of Th2-based inflammation and cytokines is presumed to increase graft rejection by making CD4+ effector T-cells resistant to regulatory T-cells (Tregs) (4). Several studies have also reported the critical role Tregs play in immune tolerance and immunosuppression (5, 6). In this report, we present a case of graft rejection reaction that correlated with aggravation of atopic dermatitis 3 years after HTx.
Case Description
We present the case of a 32-year-old man who underwent orthotropic HTx at our hospital due to dilated cardiomyopathy (DCM). The patient was diagnosed with atopic dermatitis during childhood which necessitated the use of topical drugs. At 24 years old, he noted dyspnea on exertion. Shortly after, he was diagnosed with DCM and subsequently developed severe drug-resistant heart failure. At 25 years old, a left ventricular assist device was implanted as bridge therapy for heart failure. At 29 years old, orthotropic HTx was performed at our hospital. The patient was treated with standard immunosuppression therapy consisting of cyclosporine, mycophenolate mofetil (MMF), and prednisolone. We performed endomyocardial biopsy according to our institutional protocol, which consists of examinations at the 1st, 2nd, 3rd, 4th, 6th, 8th, 10th, 12th, 18th, and 24th post-procedural weeks and the 1st, and 2nd post-procedural years. During the patient’s follow-ups, there were three events of mild acute cellular rejection (ACR) (grade 1R ISHLT2004/grade 2 ISHLT 1990) within two years, whereas in all other examinations there were no findings of ACR. In addition, anti-HLA antibodies were not detected during any of the follow-ups. There were also no signs of heart failure such as dyspnea and edema, and the immunosuppressive treatment course was stable. The dose of prednisolone was gradually reduced according to the policy of our institution and it was turned off about one year after HTx. After 3 years, the patient was hospitalized to undergo a regular endomyocardial biopsy (EMB). On admission, his vital signs were normal, with no leg edema and no jugular dilation. Of note is that his atopic dermatitis worsened from the previous winter season and six months before hospitalization. This was evidenced by erythema and scaling on the neck, precordium, and back, and erythema with scabs and exudate were found on the arms and legs. A blood test on admission revealed mild anemia. The blood counts of the other two strains were within the normal range, and the eosinophil count was normal. Liver and kidney function tests were normal. Chest X-ray showed normal heart shadow and no pleural effusion. Electrocardiogram (ECG) revealed sinus rhythm of 73 bpm with no ST-T changes. Transthoracic echocardiography showed normal left and right ventricular function, and left ventricle ejection fraction was estimated at 73% (Teichholz). Echocardiography parameters of intraventricular and posterior left ventricle wall diameters were 6 and 8 mm, respectively. The immunosuppressive drugs taken by the patient at the time of hospitalization were MMF 1,750 mg/day and cyclosporine 150 mg/day. Cyclosporine serum level (the trough value) was 145 ng/ml, which was within the optimum range. Right heart catheterization showed that the mean right atrial pressure, mean pulmonary artery wedge pressure, mean pulmonary artery pressure, and cardiac index (Fick) were 5, 11, 16 mmHg, and 3.63 L/min/m2, respectively, suggesting that intracardiac pressure was within the normal range and cardiac output was maintained. Coronary artery angiography showed no significant stenosis in the coronary arteries. On the other hand, EMB showed infiltration of multiple inflammatory cells with myocardial damage, which corresponded ACR with grade 2R (ISHLT 2004)/grade (3A ISHLT 1990) (Figure 1). To counteract the graft rejection, he was treated with a 3-day course of parenteral methylprednisolone (1,000 mg/day) and then oral prednisolone 25 mg/day, which was gradually reduced every two days. In addition, the dose of cyclosporine was increased from 150 mg/day to 160 mg/day. However, repeat EMB after 1 week also revealed similar findings of ACR with a grade of 2R (ISHLT 2004)/3A (ISHLT 1990). The patient was given steroid pulse therapy for 3 days, and MMF was shifted to everolimus 1 mg/day to intensify immunosuppression. Repeat EMB after 1 week showed the improvement of graft rejection (Grade 0). He was discharged without any overt complications. In addition, atopic dermatitis also improved by intensifying immunosuppressive drugs with topical drugs. During subsequent follow-ups, no adverse or clinical events were observed. One year after, 4 years after HTx, significant ACR was not noted [grade 1R (ISHLT 2004)/1A (ISHLT 1990)] and there was no exacerbation of atopic dermatitis.
Figure 1 Hematoxylin and eosin stain of endocardial biopsy sample featuring myocyte injury with multiple lymphocytic infiltration. [Grade2R(ISHLT 2004)/3A(ISHLT 1990)]. (A) First endocardial biopsy (B) Second endocardial biopsy.
Discussion
Previous studies have reported cases in which concomitant atopic/allergic disorders had an increased incidence of graft rejection. Previous investigations using mice have demonstrated that classic allergic disease such as airway hyperresponsiveness and allergic conjunctivitis, exacerbates corneal allograft rejection (1, 4). Nguyen et al. have indicated that the frequency of corneal graft rejection following normal-risk keratoplasty was significantly increased in patients with atopic dermatitis (2). Seung et al. have shown that acute rejection after renal transplantation is more common and severe in patients with atopy (7). However, no case reports exist about the association of atopic/allergic disease and graft rejection after HTx, and in our knowledge, this is the first report of its kind.
Several hypotheses have been proposed to explain the association between atopic/allergic disease and graft rejection. Atopic dermatitis and allergic airway inflammation are Th2-dominant allergic diseases. Th2 produces cytokines such as IL-4, which induces immunoglobulin E (IgE) production by acting on B-cells, while mast cells release cytokines such as IL-6 and tumor growth factor-beta (TGF-β) in response to the involvement of the IgE receptor (FcϵRI) complex on the cell surface (3, 8). The cytokines induced by Th2 are reported to suppress the effect of Tregs, leading to the enhancement of CD4+ effector T-cells. In studies with mice, it has been reported that IL-4 exacerbates corneal allograft rejection by making CD4+ effector T-cells resistant to Tregs (9). Tregs have been reported to play important roles in the suppression of graft rejection following organ transplant (3). From these findings, there is a possibility that the risk of rejection may increase via such T-cell responses in patients with atopic/allergic diseases. On the other hand, several reports have described the association between eosinophil and graft rejection after heart and lung transplantation (10–12). Acute graft rejection was reported to be associated with the local productions of IL-4 and IL-5 together with eosinophil infiltration (10). Several studies have reported on the impact of eosinophil on the development of graft rejection (11, 12). Eosinophil was reported to correlate with the severity of atopic dermatitis (13), and thus, might add some hints for the explanation of the association between atopy and graft rejection. However, the present case did not represent eosinophilia, so the correct explanation of the association between atopic dermatitis and graft rejection in this case had not been clarified.
For further validation of the association between previous history of atopic/allergic disease and the risk of ACR, we examined 76 patients from a cohort of previous study who underwent heart transplantation at our hospital between August 2007 and May 2017 (14). Six patients (7.9%) had a history of atopic/allergic diseases such as bronchial asthma (n = 4) and atopic dermatitis (n = 3), one patient had both atopic dermatitis and bronchial asthma (Table 1). The basic characteristics are presented in Table 1. The percentage of atopic/allergic disease was slightly low possibly owing to the selection of candidates for HTx. During the chronic phase after HTx (1–3 years), patients with atopic/allergic disease tended to have a significantly higher frequency of moderate rejection [(Grade 2R (ISHLT 2004)/3A (ISHLT 1990) or higher)] than patients without atopic/allergic disease [(p = 0.012; Fisher’s exact test), Odds ratio (95% CI) 10.73 (1.75 to 65.90)] (Figure 2). On the other hand, there was no significant difference in the frequency of moderate rejection [p = 0.40, odds ratio (95% CI) 2.67 (0.46 to 15.53)] less than 1 year after HTx. Based on the above, the risk of graft rejection, especially during the chronic phase, increases in atopic/allergic diseases. The survival curve was not significantly different between these two groups (Figure 3).
Table 1 Basic characteristics.
All With allergic disease Without allergic disease P value
(n = 76) (n = 6) (n = 70)
Age, years 40 (29–53) 44.5 (27.5–53.0) 39.5 (28.8–53.2) 0.80
Male 53 (69.7) 6 (100) 47 (67.1) 0.09
BMI, kg/m2 20.0 (17.1–23.1) 23.8 (20.9–27.2) 19.8 (17.4–23.1) 0.0075
WBC, μl 5,600 (4,200–6,850) 5,400 (3,950–10,200) 5,600 (4,200–6,750) 0.79
Eosinophils,/μl 11.2 (0–51.7) 17.3 (6.3–61.5) 10.8 (0–51.9) 0.65
Hb, g/dl 11.4 (10.4–12.8) 12.1 (10.9–13.8) 11.4 (10.2–12.8) 0.20
Plt, ×104/μl 21.8 (19.0–24.7) 22.0 (15.9–23.8) 21.8 (19.1–24.8) 0.54
eGFR, 51.6 (39.2–70.1) 45.9 (40.4–62.6) 52.4 (38.9–71.0) 0.59
ml/min/1.73m2
CRP, mg/dl 0.06 (0.02–0.2) 0.035 (0.018–0.18) 0.06 (0.02–0.25) 0.37
BNP, pg/ml 79.2 (44.0–116.5) 64.7 (44.8–88.8) 81.5 (43.7–121.9) 0.45
All variables presented as median (interquartile range) or n (%).
Age was the age at the time of the heart transplantation. Blood test data was data one year after the heart transplantation. P-values were calculated by Fisher’s exact test, t-test or Wilcoxon rank-sum test comparing those with allergic disease and without allergic disease.
BMI, body mass index; WBC, white blood cell; Hb, hemoglobin; Plt, platelet; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein; BNP, B-type natriuretic peptide.
Figure 2 Difference in the development of acute cellular rejection within one year after heart transplantation (HTx) and three years after HTx between patients with and without previous allergic disease. NS, not significant.
Figure 3 Kaplan-Meier survival curve of patients with and without previous allergic disease after heart transplantation. There was no significant difference in survival curves between two groups (Log-rank p = 0.53).
Another lingering question is that despite immunosuppressive therapy, why did the patient develop exacerbation of atopic dermatitis? Both cyclosporin and MMF have been reported to be highly effective for atopic dermatitis. However, some studies have reported paradoxical development of atopic dermatitis after solid organ transplantation (15). Ozdemir et al. demonstrated newly-developed allergies after HTx (16). In addition, some studies have reported the development of allergies after receiving immunosuppressive therapy, but there had been no report about the mechanism of action, which should be elucidated more robustly in the future.
In fact, at our institution, prednisolone is turned off within 1 year after HTx (17). If there is concern about exacerbation of rejection due to exacerbation of atopic/allergic disease as in this case, a regimen such as continuing a small amount of steroid, which will be more effective for atopic/allergic disease, might be better.
Generally speaking, late-onset ACR has been known to have more adverse clinical outcomes as compared to early-onset ACR. However, triggers for late-onset ACR have not been identified. Future studies may focus on finding out the specific causes for late-onset ACR, which can ultimately lead to improvements in the treatment for post-HTx patients.
In a limitation of this study, the chronological association between the graft rejection and the exacerbation of atopic dermatitis in this case was difficult to presume. However, it is more likely that the state of atopic dermatitis affected the state of graft rejection because the impact derived from atopic dermatitis on the systemic immune response might be greater than the impact derived from graft rejection (18). In addition, more concise evaluation of the state of atopic dermatitis might help the correct clarification of the association between atopic dermatitis and graft rejection.
Similar to this case, no reports of graft rejection due to exacerbation of atopic dermatitis have yet to be reported. Patients with a history of allergic disorders such as atopic dermatitis may be at an increased risk of developing immunological rejection after transplantation, requiring a more intensive immunosuppressive regimen and careful follow-up.
Conclusions
ACR following exacerbation of atopic dermatitis 3 years post-HTx is rare and has never been reported. This case highlights the importance of considering all factors that may contribute to graft rejection, regardless of diagnostic findings. However, it is also necessary to determine what processes are involved in this relationship.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by the institutional review board at the University of Tokyo (approval number: 2,650). The patients/participants provided their written informed consent to participate in this study.
Author Contributions
NK: Data collection, statistical analysis, and writing of the manuscript. EA: Conception of the idea, data collection, critical feedback on the manuscript, and writing of the manuscript. CB, MT, JI, MH, KN, KF, and HM: Data collection and critical feedback on the manuscript. MH, MO, and IK: Critical feedback on the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan through Grant-in-Aid 17K09488 (to EA).
Conflict of Interest
EA and MH belong to the Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, University of Tokyo, which is endowed by Actelion Pharmaceuticals Japan Ltd., Otsuka Pharmaceutical, NIPRO CORPORATION, Terumo Corp., Senko Medical Instrument Mfg., Century Medical Inc., Kinetic Concepts Inc., and St. Jude Medical.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISOLONE | DrugsGivenReaction | CC BY | 33692803 | 19,425,894 | 2021 |
What was the outcome of reaction 'Dermatitis atopic'? | Case Report: A Case of Acute Cellular Rejection Due to Atopic Dermatitis Exacerbation 3 Years After Heart Transplantation.
Little evidence has been presented about the association between previous atopic/allergic disease and graft rejection after solid organ transplantation. Thus, we present a case wherein acute cellular rejection (ACR) after heart transplantation (HTx) was noted along with exacerbation of atopic disease.
A 32-year-old man was admitted at our hospital for regular monitoring of graft rejection. He had undergone heart transplant 3 years prior due to dilated cardiomyopathy. Echocardiogram revealed good biventricular function, and no abnormal findings were found in blood sampling tests. However, biopsy showed moderate ACR [Grade 2R(ISHLT 2004)/3A(ISHLT 1990)], which required twice-repeated steroid pulses with intensified immunosuppression. Meanwhile, his atopic dermatitis, which was diagnosed before having heart failure, was getting worse for the past 6 months. The exacerbation of atopic dermatitis was presumed to be related to the development of the intractable cellular rejection.
This case suggested the association of atopic disease and graft rejection after HTx. We examined 76 patients from a cohort of previous studies who underwent HTx at our hospital, which suggested that patients with atopic/allergic disorders such as atopic dermatitis and asthma tended to have a significantly higher frequency of moderate rejection than non-allergic patients. (p = 0.012; Fisher's exact test). Our case also suggests that exacerbation of atopic dermatitis might cause graft rejection of the transplanted organ, so that it is important to carefully evaluate the risk of graft rejection if there is a previous history of atopic/allergic disease.
Introduction
Heart transplantation (HTx) is a radical treatment that saves the lives of those with end-stage heart failure. Although the surgical procedures and perioperative management methods have been established, control of acute and chronic rejection and the harmful effects of immunosuppressants remain as the biggest challenges. Previous studies have reported that through the response of the T-cells, the frequency of graft rejection increases in the presence of atopic/allergic diseases (1, 2). The pathophysiology of many atopic/allergic diseases is associated with a type 2 T helpler cell (Th2)-based inflammatory response that involves the production of cytokines such as interleukin (IL)-4, IL-5, and IL-13 (3). The untoward effect of Th2-based inflammation and cytokines is presumed to increase graft rejection by making CD4+ effector T-cells resistant to regulatory T-cells (Tregs) (4). Several studies have also reported the critical role Tregs play in immune tolerance and immunosuppression (5, 6). In this report, we present a case of graft rejection reaction that correlated with aggravation of atopic dermatitis 3 years after HTx.
Case Description
We present the case of a 32-year-old man who underwent orthotropic HTx at our hospital due to dilated cardiomyopathy (DCM). The patient was diagnosed with atopic dermatitis during childhood which necessitated the use of topical drugs. At 24 years old, he noted dyspnea on exertion. Shortly after, he was diagnosed with DCM and subsequently developed severe drug-resistant heart failure. At 25 years old, a left ventricular assist device was implanted as bridge therapy for heart failure. At 29 years old, orthotropic HTx was performed at our hospital. The patient was treated with standard immunosuppression therapy consisting of cyclosporine, mycophenolate mofetil (MMF), and prednisolone. We performed endomyocardial biopsy according to our institutional protocol, which consists of examinations at the 1st, 2nd, 3rd, 4th, 6th, 8th, 10th, 12th, 18th, and 24th post-procedural weeks and the 1st, and 2nd post-procedural years. During the patient’s follow-ups, there were three events of mild acute cellular rejection (ACR) (grade 1R ISHLT2004/grade 2 ISHLT 1990) within two years, whereas in all other examinations there were no findings of ACR. In addition, anti-HLA antibodies were not detected during any of the follow-ups. There were also no signs of heart failure such as dyspnea and edema, and the immunosuppressive treatment course was stable. The dose of prednisolone was gradually reduced according to the policy of our institution and it was turned off about one year after HTx. After 3 years, the patient was hospitalized to undergo a regular endomyocardial biopsy (EMB). On admission, his vital signs were normal, with no leg edema and no jugular dilation. Of note is that his atopic dermatitis worsened from the previous winter season and six months before hospitalization. This was evidenced by erythema and scaling on the neck, precordium, and back, and erythema with scabs and exudate were found on the arms and legs. A blood test on admission revealed mild anemia. The blood counts of the other two strains were within the normal range, and the eosinophil count was normal. Liver and kidney function tests were normal. Chest X-ray showed normal heart shadow and no pleural effusion. Electrocardiogram (ECG) revealed sinus rhythm of 73 bpm with no ST-T changes. Transthoracic echocardiography showed normal left and right ventricular function, and left ventricle ejection fraction was estimated at 73% (Teichholz). Echocardiography parameters of intraventricular and posterior left ventricle wall diameters were 6 and 8 mm, respectively. The immunosuppressive drugs taken by the patient at the time of hospitalization were MMF 1,750 mg/day and cyclosporine 150 mg/day. Cyclosporine serum level (the trough value) was 145 ng/ml, which was within the optimum range. Right heart catheterization showed that the mean right atrial pressure, mean pulmonary artery wedge pressure, mean pulmonary artery pressure, and cardiac index (Fick) were 5, 11, 16 mmHg, and 3.63 L/min/m2, respectively, suggesting that intracardiac pressure was within the normal range and cardiac output was maintained. Coronary artery angiography showed no significant stenosis in the coronary arteries. On the other hand, EMB showed infiltration of multiple inflammatory cells with myocardial damage, which corresponded ACR with grade 2R (ISHLT 2004)/grade (3A ISHLT 1990) (Figure 1). To counteract the graft rejection, he was treated with a 3-day course of parenteral methylprednisolone (1,000 mg/day) and then oral prednisolone 25 mg/day, which was gradually reduced every two days. In addition, the dose of cyclosporine was increased from 150 mg/day to 160 mg/day. However, repeat EMB after 1 week also revealed similar findings of ACR with a grade of 2R (ISHLT 2004)/3A (ISHLT 1990). The patient was given steroid pulse therapy for 3 days, and MMF was shifted to everolimus 1 mg/day to intensify immunosuppression. Repeat EMB after 1 week showed the improvement of graft rejection (Grade 0). He was discharged without any overt complications. In addition, atopic dermatitis also improved by intensifying immunosuppressive drugs with topical drugs. During subsequent follow-ups, no adverse or clinical events were observed. One year after, 4 years after HTx, significant ACR was not noted [grade 1R (ISHLT 2004)/1A (ISHLT 1990)] and there was no exacerbation of atopic dermatitis.
Figure 1 Hematoxylin and eosin stain of endocardial biopsy sample featuring myocyte injury with multiple lymphocytic infiltration. [Grade2R(ISHLT 2004)/3A(ISHLT 1990)]. (A) First endocardial biopsy (B) Second endocardial biopsy.
Discussion
Previous studies have reported cases in which concomitant atopic/allergic disorders had an increased incidence of graft rejection. Previous investigations using mice have demonstrated that classic allergic disease such as airway hyperresponsiveness and allergic conjunctivitis, exacerbates corneal allograft rejection (1, 4). Nguyen et al. have indicated that the frequency of corneal graft rejection following normal-risk keratoplasty was significantly increased in patients with atopic dermatitis (2). Seung et al. have shown that acute rejection after renal transplantation is more common and severe in patients with atopy (7). However, no case reports exist about the association of atopic/allergic disease and graft rejection after HTx, and in our knowledge, this is the first report of its kind.
Several hypotheses have been proposed to explain the association between atopic/allergic disease and graft rejection. Atopic dermatitis and allergic airway inflammation are Th2-dominant allergic diseases. Th2 produces cytokines such as IL-4, which induces immunoglobulin E (IgE) production by acting on B-cells, while mast cells release cytokines such as IL-6 and tumor growth factor-beta (TGF-β) in response to the involvement of the IgE receptor (FcϵRI) complex on the cell surface (3, 8). The cytokines induced by Th2 are reported to suppress the effect of Tregs, leading to the enhancement of CD4+ effector T-cells. In studies with mice, it has been reported that IL-4 exacerbates corneal allograft rejection by making CD4+ effector T-cells resistant to Tregs (9). Tregs have been reported to play important roles in the suppression of graft rejection following organ transplant (3). From these findings, there is a possibility that the risk of rejection may increase via such T-cell responses in patients with atopic/allergic diseases. On the other hand, several reports have described the association between eosinophil and graft rejection after heart and lung transplantation (10–12). Acute graft rejection was reported to be associated with the local productions of IL-4 and IL-5 together with eosinophil infiltration (10). Several studies have reported on the impact of eosinophil on the development of graft rejection (11, 12). Eosinophil was reported to correlate with the severity of atopic dermatitis (13), and thus, might add some hints for the explanation of the association between atopy and graft rejection. However, the present case did not represent eosinophilia, so the correct explanation of the association between atopic dermatitis and graft rejection in this case had not been clarified.
For further validation of the association between previous history of atopic/allergic disease and the risk of ACR, we examined 76 patients from a cohort of previous study who underwent heart transplantation at our hospital between August 2007 and May 2017 (14). Six patients (7.9%) had a history of atopic/allergic diseases such as bronchial asthma (n = 4) and atopic dermatitis (n = 3), one patient had both atopic dermatitis and bronchial asthma (Table 1). The basic characteristics are presented in Table 1. The percentage of atopic/allergic disease was slightly low possibly owing to the selection of candidates for HTx. During the chronic phase after HTx (1–3 years), patients with atopic/allergic disease tended to have a significantly higher frequency of moderate rejection [(Grade 2R (ISHLT 2004)/3A (ISHLT 1990) or higher)] than patients without atopic/allergic disease [(p = 0.012; Fisher’s exact test), Odds ratio (95% CI) 10.73 (1.75 to 65.90)] (Figure 2). On the other hand, there was no significant difference in the frequency of moderate rejection [p = 0.40, odds ratio (95% CI) 2.67 (0.46 to 15.53)] less than 1 year after HTx. Based on the above, the risk of graft rejection, especially during the chronic phase, increases in atopic/allergic diseases. The survival curve was not significantly different between these two groups (Figure 3).
Table 1 Basic characteristics.
All With allergic disease Without allergic disease P value
(n = 76) (n = 6) (n = 70)
Age, years 40 (29–53) 44.5 (27.5–53.0) 39.5 (28.8–53.2) 0.80
Male 53 (69.7) 6 (100) 47 (67.1) 0.09
BMI, kg/m2 20.0 (17.1–23.1) 23.8 (20.9–27.2) 19.8 (17.4–23.1) 0.0075
WBC, μl 5,600 (4,200–6,850) 5,400 (3,950–10,200) 5,600 (4,200–6,750) 0.79
Eosinophils,/μl 11.2 (0–51.7) 17.3 (6.3–61.5) 10.8 (0–51.9) 0.65
Hb, g/dl 11.4 (10.4–12.8) 12.1 (10.9–13.8) 11.4 (10.2–12.8) 0.20
Plt, ×104/μl 21.8 (19.0–24.7) 22.0 (15.9–23.8) 21.8 (19.1–24.8) 0.54
eGFR, 51.6 (39.2–70.1) 45.9 (40.4–62.6) 52.4 (38.9–71.0) 0.59
ml/min/1.73m2
CRP, mg/dl 0.06 (0.02–0.2) 0.035 (0.018–0.18) 0.06 (0.02–0.25) 0.37
BNP, pg/ml 79.2 (44.0–116.5) 64.7 (44.8–88.8) 81.5 (43.7–121.9) 0.45
All variables presented as median (interquartile range) or n (%).
Age was the age at the time of the heart transplantation. Blood test data was data one year after the heart transplantation. P-values were calculated by Fisher’s exact test, t-test or Wilcoxon rank-sum test comparing those with allergic disease and without allergic disease.
BMI, body mass index; WBC, white blood cell; Hb, hemoglobin; Plt, platelet; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein; BNP, B-type natriuretic peptide.
Figure 2 Difference in the development of acute cellular rejection within one year after heart transplantation (HTx) and three years after HTx between patients with and without previous allergic disease. NS, not significant.
Figure 3 Kaplan-Meier survival curve of patients with and without previous allergic disease after heart transplantation. There was no significant difference in survival curves between two groups (Log-rank p = 0.53).
Another lingering question is that despite immunosuppressive therapy, why did the patient develop exacerbation of atopic dermatitis? Both cyclosporin and MMF have been reported to be highly effective for atopic dermatitis. However, some studies have reported paradoxical development of atopic dermatitis after solid organ transplantation (15). Ozdemir et al. demonstrated newly-developed allergies after HTx (16). In addition, some studies have reported the development of allergies after receiving immunosuppressive therapy, but there had been no report about the mechanism of action, which should be elucidated more robustly in the future.
In fact, at our institution, prednisolone is turned off within 1 year after HTx (17). If there is concern about exacerbation of rejection due to exacerbation of atopic/allergic disease as in this case, a regimen such as continuing a small amount of steroid, which will be more effective for atopic/allergic disease, might be better.
Generally speaking, late-onset ACR has been known to have more adverse clinical outcomes as compared to early-onset ACR. However, triggers for late-onset ACR have not been identified. Future studies may focus on finding out the specific causes for late-onset ACR, which can ultimately lead to improvements in the treatment for post-HTx patients.
In a limitation of this study, the chronological association between the graft rejection and the exacerbation of atopic dermatitis in this case was difficult to presume. However, it is more likely that the state of atopic dermatitis affected the state of graft rejection because the impact derived from atopic dermatitis on the systemic immune response might be greater than the impact derived from graft rejection (18). In addition, more concise evaluation of the state of atopic dermatitis might help the correct clarification of the association between atopic dermatitis and graft rejection.
Similar to this case, no reports of graft rejection due to exacerbation of atopic dermatitis have yet to be reported. Patients with a history of allergic disorders such as atopic dermatitis may be at an increased risk of developing immunological rejection after transplantation, requiring a more intensive immunosuppressive regimen and careful follow-up.
Conclusions
ACR following exacerbation of atopic dermatitis 3 years post-HTx is rare and has never been reported. This case highlights the importance of considering all factors that may contribute to graft rejection, regardless of diagnostic findings. However, it is also necessary to determine what processes are involved in this relationship.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by the institutional review board at the University of Tokyo (approval number: 2,650). The patients/participants provided their written informed consent to participate in this study.
Author Contributions
NK: Data collection, statistical analysis, and writing of the manuscript. EA: Conception of the idea, data collection, critical feedback on the manuscript, and writing of the manuscript. CB, MT, JI, MH, KN, KF, and HM: Data collection and critical feedback on the manuscript. MH, MO, and IK: Critical feedback on the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan through Grant-in-Aid 17K09488 (to EA).
Conflict of Interest
EA and MH belong to the Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, University of Tokyo, which is endowed by Actelion Pharmaceuticals Japan Ltd., Otsuka Pharmaceutical, NIPRO CORPORATION, Terumo Corp., Senko Medical Instrument Mfg., Century Medical Inc., Kinetic Concepts Inc., and St. Jude Medical.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered | ReactionOutcome | CC BY | 33692803 | 19,425,894 | 2021 |
What was the outcome of reaction 'Transplant rejection'? | Case Report: A Case of Acute Cellular Rejection Due to Atopic Dermatitis Exacerbation 3 Years After Heart Transplantation.
Little evidence has been presented about the association between previous atopic/allergic disease and graft rejection after solid organ transplantation. Thus, we present a case wherein acute cellular rejection (ACR) after heart transplantation (HTx) was noted along with exacerbation of atopic disease.
A 32-year-old man was admitted at our hospital for regular monitoring of graft rejection. He had undergone heart transplant 3 years prior due to dilated cardiomyopathy. Echocardiogram revealed good biventricular function, and no abnormal findings were found in blood sampling tests. However, biopsy showed moderate ACR [Grade 2R(ISHLT 2004)/3A(ISHLT 1990)], which required twice-repeated steroid pulses with intensified immunosuppression. Meanwhile, his atopic dermatitis, which was diagnosed before having heart failure, was getting worse for the past 6 months. The exacerbation of atopic dermatitis was presumed to be related to the development of the intractable cellular rejection.
This case suggested the association of atopic disease and graft rejection after HTx. We examined 76 patients from a cohort of previous studies who underwent HTx at our hospital, which suggested that patients with atopic/allergic disorders such as atopic dermatitis and asthma tended to have a significantly higher frequency of moderate rejection than non-allergic patients. (p = 0.012; Fisher's exact test). Our case also suggests that exacerbation of atopic dermatitis might cause graft rejection of the transplanted organ, so that it is important to carefully evaluate the risk of graft rejection if there is a previous history of atopic/allergic disease.
Introduction
Heart transplantation (HTx) is a radical treatment that saves the lives of those with end-stage heart failure. Although the surgical procedures and perioperative management methods have been established, control of acute and chronic rejection and the harmful effects of immunosuppressants remain as the biggest challenges. Previous studies have reported that through the response of the T-cells, the frequency of graft rejection increases in the presence of atopic/allergic diseases (1, 2). The pathophysiology of many atopic/allergic diseases is associated with a type 2 T helpler cell (Th2)-based inflammatory response that involves the production of cytokines such as interleukin (IL)-4, IL-5, and IL-13 (3). The untoward effect of Th2-based inflammation and cytokines is presumed to increase graft rejection by making CD4+ effector T-cells resistant to regulatory T-cells (Tregs) (4). Several studies have also reported the critical role Tregs play in immune tolerance and immunosuppression (5, 6). In this report, we present a case of graft rejection reaction that correlated with aggravation of atopic dermatitis 3 years after HTx.
Case Description
We present the case of a 32-year-old man who underwent orthotropic HTx at our hospital due to dilated cardiomyopathy (DCM). The patient was diagnosed with atopic dermatitis during childhood which necessitated the use of topical drugs. At 24 years old, he noted dyspnea on exertion. Shortly after, he was diagnosed with DCM and subsequently developed severe drug-resistant heart failure. At 25 years old, a left ventricular assist device was implanted as bridge therapy for heart failure. At 29 years old, orthotropic HTx was performed at our hospital. The patient was treated with standard immunosuppression therapy consisting of cyclosporine, mycophenolate mofetil (MMF), and prednisolone. We performed endomyocardial biopsy according to our institutional protocol, which consists of examinations at the 1st, 2nd, 3rd, 4th, 6th, 8th, 10th, 12th, 18th, and 24th post-procedural weeks and the 1st, and 2nd post-procedural years. During the patient’s follow-ups, there were three events of mild acute cellular rejection (ACR) (grade 1R ISHLT2004/grade 2 ISHLT 1990) within two years, whereas in all other examinations there were no findings of ACR. In addition, anti-HLA antibodies were not detected during any of the follow-ups. There were also no signs of heart failure such as dyspnea and edema, and the immunosuppressive treatment course was stable. The dose of prednisolone was gradually reduced according to the policy of our institution and it was turned off about one year after HTx. After 3 years, the patient was hospitalized to undergo a regular endomyocardial biopsy (EMB). On admission, his vital signs were normal, with no leg edema and no jugular dilation. Of note is that his atopic dermatitis worsened from the previous winter season and six months before hospitalization. This was evidenced by erythema and scaling on the neck, precordium, and back, and erythema with scabs and exudate were found on the arms and legs. A blood test on admission revealed mild anemia. The blood counts of the other two strains were within the normal range, and the eosinophil count was normal. Liver and kidney function tests were normal. Chest X-ray showed normal heart shadow and no pleural effusion. Electrocardiogram (ECG) revealed sinus rhythm of 73 bpm with no ST-T changes. Transthoracic echocardiography showed normal left and right ventricular function, and left ventricle ejection fraction was estimated at 73% (Teichholz). Echocardiography parameters of intraventricular and posterior left ventricle wall diameters were 6 and 8 mm, respectively. The immunosuppressive drugs taken by the patient at the time of hospitalization were MMF 1,750 mg/day and cyclosporine 150 mg/day. Cyclosporine serum level (the trough value) was 145 ng/ml, which was within the optimum range. Right heart catheterization showed that the mean right atrial pressure, mean pulmonary artery wedge pressure, mean pulmonary artery pressure, and cardiac index (Fick) were 5, 11, 16 mmHg, and 3.63 L/min/m2, respectively, suggesting that intracardiac pressure was within the normal range and cardiac output was maintained. Coronary artery angiography showed no significant stenosis in the coronary arteries. On the other hand, EMB showed infiltration of multiple inflammatory cells with myocardial damage, which corresponded ACR with grade 2R (ISHLT 2004)/grade (3A ISHLT 1990) (Figure 1). To counteract the graft rejection, he was treated with a 3-day course of parenteral methylprednisolone (1,000 mg/day) and then oral prednisolone 25 mg/day, which was gradually reduced every two days. In addition, the dose of cyclosporine was increased from 150 mg/day to 160 mg/day. However, repeat EMB after 1 week also revealed similar findings of ACR with a grade of 2R (ISHLT 2004)/3A (ISHLT 1990). The patient was given steroid pulse therapy for 3 days, and MMF was shifted to everolimus 1 mg/day to intensify immunosuppression. Repeat EMB after 1 week showed the improvement of graft rejection (Grade 0). He was discharged without any overt complications. In addition, atopic dermatitis also improved by intensifying immunosuppressive drugs with topical drugs. During subsequent follow-ups, no adverse or clinical events were observed. One year after, 4 years after HTx, significant ACR was not noted [grade 1R (ISHLT 2004)/1A (ISHLT 1990)] and there was no exacerbation of atopic dermatitis.
Figure 1 Hematoxylin and eosin stain of endocardial biopsy sample featuring myocyte injury with multiple lymphocytic infiltration. [Grade2R(ISHLT 2004)/3A(ISHLT 1990)]. (A) First endocardial biopsy (B) Second endocardial biopsy.
Discussion
Previous studies have reported cases in which concomitant atopic/allergic disorders had an increased incidence of graft rejection. Previous investigations using mice have demonstrated that classic allergic disease such as airway hyperresponsiveness and allergic conjunctivitis, exacerbates corneal allograft rejection (1, 4). Nguyen et al. have indicated that the frequency of corneal graft rejection following normal-risk keratoplasty was significantly increased in patients with atopic dermatitis (2). Seung et al. have shown that acute rejection after renal transplantation is more common and severe in patients with atopy (7). However, no case reports exist about the association of atopic/allergic disease and graft rejection after HTx, and in our knowledge, this is the first report of its kind.
Several hypotheses have been proposed to explain the association between atopic/allergic disease and graft rejection. Atopic dermatitis and allergic airway inflammation are Th2-dominant allergic diseases. Th2 produces cytokines such as IL-4, which induces immunoglobulin E (IgE) production by acting on B-cells, while mast cells release cytokines such as IL-6 and tumor growth factor-beta (TGF-β) in response to the involvement of the IgE receptor (FcϵRI) complex on the cell surface (3, 8). The cytokines induced by Th2 are reported to suppress the effect of Tregs, leading to the enhancement of CD4+ effector T-cells. In studies with mice, it has been reported that IL-4 exacerbates corneal allograft rejection by making CD4+ effector T-cells resistant to Tregs (9). Tregs have been reported to play important roles in the suppression of graft rejection following organ transplant (3). From these findings, there is a possibility that the risk of rejection may increase via such T-cell responses in patients with atopic/allergic diseases. On the other hand, several reports have described the association between eosinophil and graft rejection after heart and lung transplantation (10–12). Acute graft rejection was reported to be associated with the local productions of IL-4 and IL-5 together with eosinophil infiltration (10). Several studies have reported on the impact of eosinophil on the development of graft rejection (11, 12). Eosinophil was reported to correlate with the severity of atopic dermatitis (13), and thus, might add some hints for the explanation of the association between atopy and graft rejection. However, the present case did not represent eosinophilia, so the correct explanation of the association between atopic dermatitis and graft rejection in this case had not been clarified.
For further validation of the association between previous history of atopic/allergic disease and the risk of ACR, we examined 76 patients from a cohort of previous study who underwent heart transplantation at our hospital between August 2007 and May 2017 (14). Six patients (7.9%) had a history of atopic/allergic diseases such as bronchial asthma (n = 4) and atopic dermatitis (n = 3), one patient had both atopic dermatitis and bronchial asthma (Table 1). The basic characteristics are presented in Table 1. The percentage of atopic/allergic disease was slightly low possibly owing to the selection of candidates for HTx. During the chronic phase after HTx (1–3 years), patients with atopic/allergic disease tended to have a significantly higher frequency of moderate rejection [(Grade 2R (ISHLT 2004)/3A (ISHLT 1990) or higher)] than patients without atopic/allergic disease [(p = 0.012; Fisher’s exact test), Odds ratio (95% CI) 10.73 (1.75 to 65.90)] (Figure 2). On the other hand, there was no significant difference in the frequency of moderate rejection [p = 0.40, odds ratio (95% CI) 2.67 (0.46 to 15.53)] less than 1 year after HTx. Based on the above, the risk of graft rejection, especially during the chronic phase, increases in atopic/allergic diseases. The survival curve was not significantly different between these two groups (Figure 3).
Table 1 Basic characteristics.
All With allergic disease Without allergic disease P value
(n = 76) (n = 6) (n = 70)
Age, years 40 (29–53) 44.5 (27.5–53.0) 39.5 (28.8–53.2) 0.80
Male 53 (69.7) 6 (100) 47 (67.1) 0.09
BMI, kg/m2 20.0 (17.1–23.1) 23.8 (20.9–27.2) 19.8 (17.4–23.1) 0.0075
WBC, μl 5,600 (4,200–6,850) 5,400 (3,950–10,200) 5,600 (4,200–6,750) 0.79
Eosinophils,/μl 11.2 (0–51.7) 17.3 (6.3–61.5) 10.8 (0–51.9) 0.65
Hb, g/dl 11.4 (10.4–12.8) 12.1 (10.9–13.8) 11.4 (10.2–12.8) 0.20
Plt, ×104/μl 21.8 (19.0–24.7) 22.0 (15.9–23.8) 21.8 (19.1–24.8) 0.54
eGFR, 51.6 (39.2–70.1) 45.9 (40.4–62.6) 52.4 (38.9–71.0) 0.59
ml/min/1.73m2
CRP, mg/dl 0.06 (0.02–0.2) 0.035 (0.018–0.18) 0.06 (0.02–0.25) 0.37
BNP, pg/ml 79.2 (44.0–116.5) 64.7 (44.8–88.8) 81.5 (43.7–121.9) 0.45
All variables presented as median (interquartile range) or n (%).
Age was the age at the time of the heart transplantation. Blood test data was data one year after the heart transplantation. P-values were calculated by Fisher’s exact test, t-test or Wilcoxon rank-sum test comparing those with allergic disease and without allergic disease.
BMI, body mass index; WBC, white blood cell; Hb, hemoglobin; Plt, platelet; eGFR, estimated glomerular filtration rate; CRP, C-reactive protein; BNP, B-type natriuretic peptide.
Figure 2 Difference in the development of acute cellular rejection within one year after heart transplantation (HTx) and three years after HTx between patients with and without previous allergic disease. NS, not significant.
Figure 3 Kaplan-Meier survival curve of patients with and without previous allergic disease after heart transplantation. There was no significant difference in survival curves between two groups (Log-rank p = 0.53).
Another lingering question is that despite immunosuppressive therapy, why did the patient develop exacerbation of atopic dermatitis? Both cyclosporin and MMF have been reported to be highly effective for atopic dermatitis. However, some studies have reported paradoxical development of atopic dermatitis after solid organ transplantation (15). Ozdemir et al. demonstrated newly-developed allergies after HTx (16). In addition, some studies have reported the development of allergies after receiving immunosuppressive therapy, but there had been no report about the mechanism of action, which should be elucidated more robustly in the future.
In fact, at our institution, prednisolone is turned off within 1 year after HTx (17). If there is concern about exacerbation of rejection due to exacerbation of atopic/allergic disease as in this case, a regimen such as continuing a small amount of steroid, which will be more effective for atopic/allergic disease, might be better.
Generally speaking, late-onset ACR has been known to have more adverse clinical outcomes as compared to early-onset ACR. However, triggers for late-onset ACR have not been identified. Future studies may focus on finding out the specific causes for late-onset ACR, which can ultimately lead to improvements in the treatment for post-HTx patients.
In a limitation of this study, the chronological association between the graft rejection and the exacerbation of atopic dermatitis in this case was difficult to presume. However, it is more likely that the state of atopic dermatitis affected the state of graft rejection because the impact derived from atopic dermatitis on the systemic immune response might be greater than the impact derived from graft rejection (18). In addition, more concise evaluation of the state of atopic dermatitis might help the correct clarification of the association between atopic dermatitis and graft rejection.
Similar to this case, no reports of graft rejection due to exacerbation of atopic dermatitis have yet to be reported. Patients with a history of allergic disorders such as atopic dermatitis may be at an increased risk of developing immunological rejection after transplantation, requiring a more intensive immunosuppressive regimen and careful follow-up.
Conclusions
ACR following exacerbation of atopic dermatitis 3 years post-HTx is rare and has never been reported. This case highlights the importance of considering all factors that may contribute to graft rejection, regardless of diagnostic findings. However, it is also necessary to determine what processes are involved in this relationship.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by the institutional review board at the University of Tokyo (approval number: 2,650). The patients/participants provided their written informed consent to participate in this study.
Author Contributions
NK: Data collection, statistical analysis, and writing of the manuscript. EA: Conception of the idea, data collection, critical feedback on the manuscript, and writing of the manuscript. CB, MT, JI, MH, KN, KF, and HM: Data collection and critical feedback on the manuscript. MH, MO, and IK: Critical feedback on the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan through Grant-in-Aid 17K09488 (to EA).
Conflict of Interest
EA and MH belong to the Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, University of Tokyo, which is endowed by Actelion Pharmaceuticals Japan Ltd., Otsuka Pharmaceutical, NIPRO CORPORATION, Terumo Corp., Senko Medical Instrument Mfg., Century Medical Inc., Kinetic Concepts Inc., and St. Jude Medical.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered | ReactionOutcome | CC BY | 33692803 | 19,425,894 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atrioventricular block second degree'. | A Case of Reversible Atrioventricular Block Potentially Associated with Atenolol-Induced Hyperkalemia.
Potassium is an extracellular ion that plays an important role in the electrophysiological function of the heart. Any change in the extracellular concentration of potassium can have a marked impression upon cardiac electrophysiology. Underlying kidney disease, certain medical conditions, dietary indiscretions, and medications can precipitate hyperkalemia. Drug-induced hyperkalemia is one of the most important causes of increased serum potassium in everyday clinical practice. Hyperkalemia can lead to various life-threatening dysrhythmias and if left untreated, it will ultimately cause ventricular arrhythmias and asystole. This case report describes an end-stage renal disease (ESRD) patient taking atenolol who presented with hyperkalemia and type II second degree atrioventricular (AV) block. He presented with hyperkalemia when atenolol was introduced and normalized when atenolol was discontinued. The heart block completely resolved after treatment of hyperkalemia.
Introduction
Hyperkalemia is a potentially life-threatening condition that is defined as a serum potassium level above a reference range, usually greater than 5.0 mEq/L; severe hyperkalemia is often defined as a level greater than 6.0 mEq/L. Prescribed medications, over-the-counter drugs, and nutritional supplements that can affect the potassium levels are used by many patients. Although most of these products are well tolerated, drug-induced hyperkalemia may develop in patients with underlying renal impairment or other abnormalities in potassium handling [1]. In hospitalized patients, the incidence of hyperkalemia ranges from 1.3% to 10%, with a mortality rate of 1 per 1,000 patients [2]. Drug-induced hyperkalemia is one of the most important causes in everyday clinical practice and has been identified as a primary contributing factor of hyperkalemia in 35%-75% of hospitalized patients [2]. Beta-blockers are postulated to induce hyperkalemia by suppressing catecholamine stimulated renin release, decrease aldosterone levels and impair cellular uptake of potassium [3]. Beta-blocker can increase serum potassium level by 1 mmol/L or more in end-stage renal disease (ESRD) [2]. Hyperkalemia is more commonly seen with nonselective rather than with cardio-selective beta-blockers [2]. However, there is one reported case of atenolol-induced hyperkalemia in the medical literature [4]. The duration of hyperkalemia can be fairly prolonged with advanced chronic kidney disease, particularly when renally cleared beta-blockers such as atenolol, are administered [2].
There is one reported case of complete heart block induced by hyperkalemia in an ESRD patient that completely resolved to normal with hyperkalemia treatment but months later developed permanent right bundle branch block (RBBB) and left anterior fascicular block [5]. The uniqueness of our case is that although there can be various ranges of heart block induced by hyperkalemia, there is no reported case so far presenting with reversible atrioventricular (AV) block potentially associated with atenolol-induced hyperkalemia in a patient without documented heart disease.
Case presentation
A 64-year-old Asian male with a past medical history of hypertension, type 2 diabetes mellitus, anemia, and ESRD on hemodialysis was referred by the dialysis center for evaluation after the patient was found to have a heart rate in the 30s and was brought to the emergency department (ED) by ambulance. He receives hemodialysis at an outpatient dialysis center three days a week, reported to be compliant, and did not miss any session. However, when he went to the dialysis center, he was found to have low blood pressure (BP) of 88/47 mmHg and a heart rate (HR) of 45 bpm. Leg elevation and inhalational oxygen via nasal cannula were provided but vitals rechecked after 30 minutes revealed BP 145/68 mmHg and HR 36/min. Therefore, emergency medical services (EMS) was activated, and the patient was brought to the ED.
Vitals on triage in the ED were notable for BP 108/54 mmHg, HR 33 bpm, oxygen saturation 100% on 2 liters nasal cannula (NC). He was alert, awake, and answered questions appropriately. He was not aware of his slow heart rate, but he complained of feeling dizzy on and off over the past two days. He denied chest pain, palpitation, shortness of breath, and spells of blackout. Stat EKG was done which showed ventricular rate of 37 bpm, PR interval 284 ms, QRS duration of 154 ms, QTc 466 ms. Fingerstick blood glucose was 195 mg/dl. Further interpretation of EKG revealed second degree 2:1 AV conduction with wide QRS suggestive of type II second degree AV heart block and peaked T wake (Figure 1). This is not his first-time presentation with a similar picture. His past medical records showed that he was admitted three times over the past two years with a similar presentation of hyperkalemia and heart block, one time with first degree AV block, another two times with type I second degree AV block, all resolved to normal sinus rhythm after potassium was normalized. His medications list was significant for atenolol which was discontinued in his previous admissions but was again prescribed a few days before his presentation to the ED.
Figure 1 EKG changes before treatment
His physical examination was unremarkable except for severe bradycardia and cool and clammy extremities. On the cardiac monitor, his heart rate was ranging between 30 bpm to 35 bpm. In view of his previous presentations and EKG findings, he was given calcium gluconate 1 gram slow intravenous (IV) stat, 10 units of IV regular insulin, 25 grams of dextrose 50%, and 12 milliliters of albuterol nebulizer while waiting for blood tests results.
While receiving treatment, basic labs including plasma potassium were sent. The results came back with serum potassium of 8.7 mmol/L, plasma potassium of 8.6 mmol/L. Other chemistries were sodium 135 mmol/L, chloride 96 mmol/L, bicarbonate 23 mmol/L, blood urea nitrogen (BUN) 78 mg/dl, creatinine 14.54 mg/dl, glucose 192 mg/dl, magnesium 2.6 mg/dl, and phosphorous 7.3 mg/dl.
His heart rate showed slight improvement after receiving treatment. Nephrology team recommended emergency hemodialysis. He was also given 30 grams of Kayexylate orally, an additional 2 grams of calcium gluconate slow IV while awaiting hemodialysis set up. He received a total of four hours of hemodialysis with 1K bath for the first 2.5 hours followed by 2K bath for the remaining treatment. Two hours post-dialysis, potassium came back 3.3 mmol/L.
The patient was admitted to the telemetry unit with nephrology on board. His hyperkalemia was thought to be secondary to atenolol considering his multiple presentations provoked by the reintroduction of atenolol. His cardiac enzyme was not elevated. Continuous cardiac monitoring was uneventful. At the time of discharge, his potassium level was 4.6 mmol/L. Beta-blocker was held throughout his hospital stay and also not continued upon discharge. His EKG on the day of his discharge demonstrated complete resolution of the previously seen type II second degree AV block pattern. EKG showed a rate of 72 bpm, PR interval 156 ms, normal sinus rhythm, and slightly prolonged QTc 462 ms (Figure 2).
Figure 2 Normal sinus rhythm after treatment
Discussion
This case depicts an unusual presentation of atenolol-induced hyperkalemia causing type II second degree heart block that resolves completely to normal after correction of hyperkalemia, and discontinuation of atenolol. In this patient, who is reported to have started taking atenolol a few days before presentation, it is reasonable to believe that his hyperkalemia could be induced by atenolol, and heart block could be contributed by atenolol-induced hyperkalemia. For some reason, even though atenolol was discontinued upon previous discharges because of similar presentation, it was again prescribed by different doctors. Contributing factors could be lost to follow up upon discharge, no dedicated primary doctor, language barrier to some extent even though language line was properly used, and lack of health knowledge. In view of his recurrent presentation of hyperkalemia-induced heart block, electrophysiologic studies would be warranted to rule out any underlying pathology. However, the disappearance of hyperkalemia-induced heart block with hyperkalemia treatment and discontinuation of atenolol, the absence of any other acute causes of AV block make it seem unlikely. The resolution of type II second degree heart block to sinus rhythm after treatment of hyperkalemia and hemodialysis also suggest that atenolol-induced hyperkalemia is responsible for this high-grade AV block.
Hyperkalemia can lower cell-resting action potential and causes abnormal heart muscle function resulting in EKG findings initially with tall and tented T wave, loss of P wave, prolong PR interval, widened QRS complex, and eventually sine wave before the heart stops [6]. Varying degrees of heart block can also happen with this electrolyte disturbance but advanced heart blocks such as second- and third-degree AV blocks are generally found only in patients with underlying heart disease, heart failures, or preexisting conduction abnormalities. It was reasoned that underlying coronary artery or diffuse cardiac disease have already destroyed the AV node and His-Purkinje system to a certain extent that hyperkalemia can aggravate pre-existing diagnosed or undiagnosed conduction defects [7].
Beta-blocker can increase serum potassium level by 1 mmol/L or more in ESRD [2]. Hyperkalemia was mainly seen with nonselective rather than with cardio-selective beta-blockers [2]. However, there is one reported case of atenolol-induced hyperkalemia in the medical literature [4]. Severe hyperkalemia as a complication of timolol, a topically applied beta-blocker, has also been reported [2]. The duration of hyperkalemia can be fairly prolonged with advanced chronic kidney disease, particularly when renally cleared beta-blockers such as atenolol, are administered [2].
In addition to discontinuing medications that can increase potassium and removal of dietary sources of potassium intake, available treatments for hyperkalemia include intravenous calcium to ameliorate cardiac toxicity if present, intravenous insulin, glucose, nebulized beta-adrenergic agonist, oral gastrointestinal cation exchangers, loop diuretics, and emergency hemodialysis as a last resort for patients with severe renal impairment or for patients with potentially lethal hyperkalemia not responding to conservative measures [8].
This patient is reported to be compliant with hemodialysis. There was no significant modification of his diet over the past years as per the patient. This is his fourth presentation with hyperkalemia, the last two times also assumed to be provoked by the reintroduction of atenolol when studied retrospectively. Every time upon discharge, he was always lost to follow up and presented with a similar problem. Upon looking back into his past records, atenolol was discontinued every time, and he was explained the reason, but it was again prescribed by different doctors a few days before his presentation to the ED. Upon discharge this time, his dedicated primary care physician was contacted and explained the situation, and the patient was also counseled to follow up with a particular primary care physician for comprehensive care.
Because of the absence of any documented underlying cardiac disease and the correlation of recent reintroduction of beta-blocker, we would like to propose that type II second degree heart block was caused by atenolol-induced hyperkalemia. Albeit atenolol can cause heart block as well; AV block is commonly related to drugs but rarely caused by drugs [9].
Conclusions
Even though ESRD patients are already very susceptible to hyperkalemia, in our patient who is compliant to hemodialysis, we should also look into other possible causes of this electrolyte disturbance. Beta-blockers are commonly used for the treatment of hypertension. Physicians should be aware of the medications that can precipitate hyperkalemia, patient characteristics with a higher risk of hyperkalemia, the range of dysrhythmias attributed to hyperkalemia, and implementing treatments without waiting for lab results if necessary.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | ATENOLOL | DrugsGivenReaction | CC BY | 33692921 | 19,066,921 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperkalaemia'. | A Case of Reversible Atrioventricular Block Potentially Associated with Atenolol-Induced Hyperkalemia.
Potassium is an extracellular ion that plays an important role in the electrophysiological function of the heart. Any change in the extracellular concentration of potassium can have a marked impression upon cardiac electrophysiology. Underlying kidney disease, certain medical conditions, dietary indiscretions, and medications can precipitate hyperkalemia. Drug-induced hyperkalemia is one of the most important causes of increased serum potassium in everyday clinical practice. Hyperkalemia can lead to various life-threatening dysrhythmias and if left untreated, it will ultimately cause ventricular arrhythmias and asystole. This case report describes an end-stage renal disease (ESRD) patient taking atenolol who presented with hyperkalemia and type II second degree atrioventricular (AV) block. He presented with hyperkalemia when atenolol was introduced and normalized when atenolol was discontinued. The heart block completely resolved after treatment of hyperkalemia.
Introduction
Hyperkalemia is a potentially life-threatening condition that is defined as a serum potassium level above a reference range, usually greater than 5.0 mEq/L; severe hyperkalemia is often defined as a level greater than 6.0 mEq/L. Prescribed medications, over-the-counter drugs, and nutritional supplements that can affect the potassium levels are used by many patients. Although most of these products are well tolerated, drug-induced hyperkalemia may develop in patients with underlying renal impairment or other abnormalities in potassium handling [1]. In hospitalized patients, the incidence of hyperkalemia ranges from 1.3% to 10%, with a mortality rate of 1 per 1,000 patients [2]. Drug-induced hyperkalemia is one of the most important causes in everyday clinical practice and has been identified as a primary contributing factor of hyperkalemia in 35%-75% of hospitalized patients [2]. Beta-blockers are postulated to induce hyperkalemia by suppressing catecholamine stimulated renin release, decrease aldosterone levels and impair cellular uptake of potassium [3]. Beta-blocker can increase serum potassium level by 1 mmol/L or more in end-stage renal disease (ESRD) [2]. Hyperkalemia is more commonly seen with nonselective rather than with cardio-selective beta-blockers [2]. However, there is one reported case of atenolol-induced hyperkalemia in the medical literature [4]. The duration of hyperkalemia can be fairly prolonged with advanced chronic kidney disease, particularly when renally cleared beta-blockers such as atenolol, are administered [2].
There is one reported case of complete heart block induced by hyperkalemia in an ESRD patient that completely resolved to normal with hyperkalemia treatment but months later developed permanent right bundle branch block (RBBB) and left anterior fascicular block [5]. The uniqueness of our case is that although there can be various ranges of heart block induced by hyperkalemia, there is no reported case so far presenting with reversible atrioventricular (AV) block potentially associated with atenolol-induced hyperkalemia in a patient without documented heart disease.
Case presentation
A 64-year-old Asian male with a past medical history of hypertension, type 2 diabetes mellitus, anemia, and ESRD on hemodialysis was referred by the dialysis center for evaluation after the patient was found to have a heart rate in the 30s and was brought to the emergency department (ED) by ambulance. He receives hemodialysis at an outpatient dialysis center three days a week, reported to be compliant, and did not miss any session. However, when he went to the dialysis center, he was found to have low blood pressure (BP) of 88/47 mmHg and a heart rate (HR) of 45 bpm. Leg elevation and inhalational oxygen via nasal cannula were provided but vitals rechecked after 30 minutes revealed BP 145/68 mmHg and HR 36/min. Therefore, emergency medical services (EMS) was activated, and the patient was brought to the ED.
Vitals on triage in the ED were notable for BP 108/54 mmHg, HR 33 bpm, oxygen saturation 100% on 2 liters nasal cannula (NC). He was alert, awake, and answered questions appropriately. He was not aware of his slow heart rate, but he complained of feeling dizzy on and off over the past two days. He denied chest pain, palpitation, shortness of breath, and spells of blackout. Stat EKG was done which showed ventricular rate of 37 bpm, PR interval 284 ms, QRS duration of 154 ms, QTc 466 ms. Fingerstick blood glucose was 195 mg/dl. Further interpretation of EKG revealed second degree 2:1 AV conduction with wide QRS suggestive of type II second degree AV heart block and peaked T wake (Figure 1). This is not his first-time presentation with a similar picture. His past medical records showed that he was admitted three times over the past two years with a similar presentation of hyperkalemia and heart block, one time with first degree AV block, another two times with type I second degree AV block, all resolved to normal sinus rhythm after potassium was normalized. His medications list was significant for atenolol which was discontinued in his previous admissions but was again prescribed a few days before his presentation to the ED.
Figure 1 EKG changes before treatment
His physical examination was unremarkable except for severe bradycardia and cool and clammy extremities. On the cardiac monitor, his heart rate was ranging between 30 bpm to 35 bpm. In view of his previous presentations and EKG findings, he was given calcium gluconate 1 gram slow intravenous (IV) stat, 10 units of IV regular insulin, 25 grams of dextrose 50%, and 12 milliliters of albuterol nebulizer while waiting for blood tests results.
While receiving treatment, basic labs including plasma potassium were sent. The results came back with serum potassium of 8.7 mmol/L, plasma potassium of 8.6 mmol/L. Other chemistries were sodium 135 mmol/L, chloride 96 mmol/L, bicarbonate 23 mmol/L, blood urea nitrogen (BUN) 78 mg/dl, creatinine 14.54 mg/dl, glucose 192 mg/dl, magnesium 2.6 mg/dl, and phosphorous 7.3 mg/dl.
His heart rate showed slight improvement after receiving treatment. Nephrology team recommended emergency hemodialysis. He was also given 30 grams of Kayexylate orally, an additional 2 grams of calcium gluconate slow IV while awaiting hemodialysis set up. He received a total of four hours of hemodialysis with 1K bath for the first 2.5 hours followed by 2K bath for the remaining treatment. Two hours post-dialysis, potassium came back 3.3 mmol/L.
The patient was admitted to the telemetry unit with nephrology on board. His hyperkalemia was thought to be secondary to atenolol considering his multiple presentations provoked by the reintroduction of atenolol. His cardiac enzyme was not elevated. Continuous cardiac monitoring was uneventful. At the time of discharge, his potassium level was 4.6 mmol/L. Beta-blocker was held throughout his hospital stay and also not continued upon discharge. His EKG on the day of his discharge demonstrated complete resolution of the previously seen type II second degree AV block pattern. EKG showed a rate of 72 bpm, PR interval 156 ms, normal sinus rhythm, and slightly prolonged QTc 462 ms (Figure 2).
Figure 2 Normal sinus rhythm after treatment
Discussion
This case depicts an unusual presentation of atenolol-induced hyperkalemia causing type II second degree heart block that resolves completely to normal after correction of hyperkalemia, and discontinuation of atenolol. In this patient, who is reported to have started taking atenolol a few days before presentation, it is reasonable to believe that his hyperkalemia could be induced by atenolol, and heart block could be contributed by atenolol-induced hyperkalemia. For some reason, even though atenolol was discontinued upon previous discharges because of similar presentation, it was again prescribed by different doctors. Contributing factors could be lost to follow up upon discharge, no dedicated primary doctor, language barrier to some extent even though language line was properly used, and lack of health knowledge. In view of his recurrent presentation of hyperkalemia-induced heart block, electrophysiologic studies would be warranted to rule out any underlying pathology. However, the disappearance of hyperkalemia-induced heart block with hyperkalemia treatment and discontinuation of atenolol, the absence of any other acute causes of AV block make it seem unlikely. The resolution of type II second degree heart block to sinus rhythm after treatment of hyperkalemia and hemodialysis also suggest that atenolol-induced hyperkalemia is responsible for this high-grade AV block.
Hyperkalemia can lower cell-resting action potential and causes abnormal heart muscle function resulting in EKG findings initially with tall and tented T wave, loss of P wave, prolong PR interval, widened QRS complex, and eventually sine wave before the heart stops [6]. Varying degrees of heart block can also happen with this electrolyte disturbance but advanced heart blocks such as second- and third-degree AV blocks are generally found only in patients with underlying heart disease, heart failures, or preexisting conduction abnormalities. It was reasoned that underlying coronary artery or diffuse cardiac disease have already destroyed the AV node and His-Purkinje system to a certain extent that hyperkalemia can aggravate pre-existing diagnosed or undiagnosed conduction defects [7].
Beta-blocker can increase serum potassium level by 1 mmol/L or more in ESRD [2]. Hyperkalemia was mainly seen with nonselective rather than with cardio-selective beta-blockers [2]. However, there is one reported case of atenolol-induced hyperkalemia in the medical literature [4]. Severe hyperkalemia as a complication of timolol, a topically applied beta-blocker, has also been reported [2]. The duration of hyperkalemia can be fairly prolonged with advanced chronic kidney disease, particularly when renally cleared beta-blockers such as atenolol, are administered [2].
In addition to discontinuing medications that can increase potassium and removal of dietary sources of potassium intake, available treatments for hyperkalemia include intravenous calcium to ameliorate cardiac toxicity if present, intravenous insulin, glucose, nebulized beta-adrenergic agonist, oral gastrointestinal cation exchangers, loop diuretics, and emergency hemodialysis as a last resort for patients with severe renal impairment or for patients with potentially lethal hyperkalemia not responding to conservative measures [8].
This patient is reported to be compliant with hemodialysis. There was no significant modification of his diet over the past years as per the patient. This is his fourth presentation with hyperkalemia, the last two times also assumed to be provoked by the reintroduction of atenolol when studied retrospectively. Every time upon discharge, he was always lost to follow up and presented with a similar problem. Upon looking back into his past records, atenolol was discontinued every time, and he was explained the reason, but it was again prescribed by different doctors a few days before his presentation to the ED. Upon discharge this time, his dedicated primary care physician was contacted and explained the situation, and the patient was also counseled to follow up with a particular primary care physician for comprehensive care.
Because of the absence of any documented underlying cardiac disease and the correlation of recent reintroduction of beta-blocker, we would like to propose that type II second degree heart block was caused by atenolol-induced hyperkalemia. Albeit atenolol can cause heart block as well; AV block is commonly related to drugs but rarely caused by drugs [9].
Conclusions
Even though ESRD patients are already very susceptible to hyperkalemia, in our patient who is compliant to hemodialysis, we should also look into other possible causes of this electrolyte disturbance. Beta-blockers are commonly used for the treatment of hypertension. Physicians should be aware of the medications that can precipitate hyperkalemia, patient characteristics with a higher risk of hyperkalemia, the range of dysrhythmias attributed to hyperkalemia, and implementing treatments without waiting for lab results if necessary.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | ATENOLOL | DrugsGivenReaction | CC BY | 33692921 | 19,066,921 | 2021-02-05 |
What was the outcome of reaction 'Atrioventricular block second degree'? | A Case of Reversible Atrioventricular Block Potentially Associated with Atenolol-Induced Hyperkalemia.
Potassium is an extracellular ion that plays an important role in the electrophysiological function of the heart. Any change in the extracellular concentration of potassium can have a marked impression upon cardiac electrophysiology. Underlying kidney disease, certain medical conditions, dietary indiscretions, and medications can precipitate hyperkalemia. Drug-induced hyperkalemia is one of the most important causes of increased serum potassium in everyday clinical practice. Hyperkalemia can lead to various life-threatening dysrhythmias and if left untreated, it will ultimately cause ventricular arrhythmias and asystole. This case report describes an end-stage renal disease (ESRD) patient taking atenolol who presented with hyperkalemia and type II second degree atrioventricular (AV) block. He presented with hyperkalemia when atenolol was introduced and normalized when atenolol was discontinued. The heart block completely resolved after treatment of hyperkalemia.
Introduction
Hyperkalemia is a potentially life-threatening condition that is defined as a serum potassium level above a reference range, usually greater than 5.0 mEq/L; severe hyperkalemia is often defined as a level greater than 6.0 mEq/L. Prescribed medications, over-the-counter drugs, and nutritional supplements that can affect the potassium levels are used by many patients. Although most of these products are well tolerated, drug-induced hyperkalemia may develop in patients with underlying renal impairment or other abnormalities in potassium handling [1]. In hospitalized patients, the incidence of hyperkalemia ranges from 1.3% to 10%, with a mortality rate of 1 per 1,000 patients [2]. Drug-induced hyperkalemia is one of the most important causes in everyday clinical practice and has been identified as a primary contributing factor of hyperkalemia in 35%-75% of hospitalized patients [2]. Beta-blockers are postulated to induce hyperkalemia by suppressing catecholamine stimulated renin release, decrease aldosterone levels and impair cellular uptake of potassium [3]. Beta-blocker can increase serum potassium level by 1 mmol/L or more in end-stage renal disease (ESRD) [2]. Hyperkalemia is more commonly seen with nonselective rather than with cardio-selective beta-blockers [2]. However, there is one reported case of atenolol-induced hyperkalemia in the medical literature [4]. The duration of hyperkalemia can be fairly prolonged with advanced chronic kidney disease, particularly when renally cleared beta-blockers such as atenolol, are administered [2].
There is one reported case of complete heart block induced by hyperkalemia in an ESRD patient that completely resolved to normal with hyperkalemia treatment but months later developed permanent right bundle branch block (RBBB) and left anterior fascicular block [5]. The uniqueness of our case is that although there can be various ranges of heart block induced by hyperkalemia, there is no reported case so far presenting with reversible atrioventricular (AV) block potentially associated with atenolol-induced hyperkalemia in a patient without documented heart disease.
Case presentation
A 64-year-old Asian male with a past medical history of hypertension, type 2 diabetes mellitus, anemia, and ESRD on hemodialysis was referred by the dialysis center for evaluation after the patient was found to have a heart rate in the 30s and was brought to the emergency department (ED) by ambulance. He receives hemodialysis at an outpatient dialysis center three days a week, reported to be compliant, and did not miss any session. However, when he went to the dialysis center, he was found to have low blood pressure (BP) of 88/47 mmHg and a heart rate (HR) of 45 bpm. Leg elevation and inhalational oxygen via nasal cannula were provided but vitals rechecked after 30 minutes revealed BP 145/68 mmHg and HR 36/min. Therefore, emergency medical services (EMS) was activated, and the patient was brought to the ED.
Vitals on triage in the ED were notable for BP 108/54 mmHg, HR 33 bpm, oxygen saturation 100% on 2 liters nasal cannula (NC). He was alert, awake, and answered questions appropriately. He was not aware of his slow heart rate, but he complained of feeling dizzy on and off over the past two days. He denied chest pain, palpitation, shortness of breath, and spells of blackout. Stat EKG was done which showed ventricular rate of 37 bpm, PR interval 284 ms, QRS duration of 154 ms, QTc 466 ms. Fingerstick blood glucose was 195 mg/dl. Further interpretation of EKG revealed second degree 2:1 AV conduction with wide QRS suggestive of type II second degree AV heart block and peaked T wake (Figure 1). This is not his first-time presentation with a similar picture. His past medical records showed that he was admitted three times over the past two years with a similar presentation of hyperkalemia and heart block, one time with first degree AV block, another two times with type I second degree AV block, all resolved to normal sinus rhythm after potassium was normalized. His medications list was significant for atenolol which was discontinued in his previous admissions but was again prescribed a few days before his presentation to the ED.
Figure 1 EKG changes before treatment
His physical examination was unremarkable except for severe bradycardia and cool and clammy extremities. On the cardiac monitor, his heart rate was ranging between 30 bpm to 35 bpm. In view of his previous presentations and EKG findings, he was given calcium gluconate 1 gram slow intravenous (IV) stat, 10 units of IV regular insulin, 25 grams of dextrose 50%, and 12 milliliters of albuterol nebulizer while waiting for blood tests results.
While receiving treatment, basic labs including plasma potassium were sent. The results came back with serum potassium of 8.7 mmol/L, plasma potassium of 8.6 mmol/L. Other chemistries were sodium 135 mmol/L, chloride 96 mmol/L, bicarbonate 23 mmol/L, blood urea nitrogen (BUN) 78 mg/dl, creatinine 14.54 mg/dl, glucose 192 mg/dl, magnesium 2.6 mg/dl, and phosphorous 7.3 mg/dl.
His heart rate showed slight improvement after receiving treatment. Nephrology team recommended emergency hemodialysis. He was also given 30 grams of Kayexylate orally, an additional 2 grams of calcium gluconate slow IV while awaiting hemodialysis set up. He received a total of four hours of hemodialysis with 1K bath for the first 2.5 hours followed by 2K bath for the remaining treatment. Two hours post-dialysis, potassium came back 3.3 mmol/L.
The patient was admitted to the telemetry unit with nephrology on board. His hyperkalemia was thought to be secondary to atenolol considering his multiple presentations provoked by the reintroduction of atenolol. His cardiac enzyme was not elevated. Continuous cardiac monitoring was uneventful. At the time of discharge, his potassium level was 4.6 mmol/L. Beta-blocker was held throughout his hospital stay and also not continued upon discharge. His EKG on the day of his discharge demonstrated complete resolution of the previously seen type II second degree AV block pattern. EKG showed a rate of 72 bpm, PR interval 156 ms, normal sinus rhythm, and slightly prolonged QTc 462 ms (Figure 2).
Figure 2 Normal sinus rhythm after treatment
Discussion
This case depicts an unusual presentation of atenolol-induced hyperkalemia causing type II second degree heart block that resolves completely to normal after correction of hyperkalemia, and discontinuation of atenolol. In this patient, who is reported to have started taking atenolol a few days before presentation, it is reasonable to believe that his hyperkalemia could be induced by atenolol, and heart block could be contributed by atenolol-induced hyperkalemia. For some reason, even though atenolol was discontinued upon previous discharges because of similar presentation, it was again prescribed by different doctors. Contributing factors could be lost to follow up upon discharge, no dedicated primary doctor, language barrier to some extent even though language line was properly used, and lack of health knowledge. In view of his recurrent presentation of hyperkalemia-induced heart block, electrophysiologic studies would be warranted to rule out any underlying pathology. However, the disappearance of hyperkalemia-induced heart block with hyperkalemia treatment and discontinuation of atenolol, the absence of any other acute causes of AV block make it seem unlikely. The resolution of type II second degree heart block to sinus rhythm after treatment of hyperkalemia and hemodialysis also suggest that atenolol-induced hyperkalemia is responsible for this high-grade AV block.
Hyperkalemia can lower cell-resting action potential and causes abnormal heart muscle function resulting in EKG findings initially with tall and tented T wave, loss of P wave, prolong PR interval, widened QRS complex, and eventually sine wave before the heart stops [6]. Varying degrees of heart block can also happen with this electrolyte disturbance but advanced heart blocks such as second- and third-degree AV blocks are generally found only in patients with underlying heart disease, heart failures, or preexisting conduction abnormalities. It was reasoned that underlying coronary artery or diffuse cardiac disease have already destroyed the AV node and His-Purkinje system to a certain extent that hyperkalemia can aggravate pre-existing diagnosed or undiagnosed conduction defects [7].
Beta-blocker can increase serum potassium level by 1 mmol/L or more in ESRD [2]. Hyperkalemia was mainly seen with nonselective rather than with cardio-selective beta-blockers [2]. However, there is one reported case of atenolol-induced hyperkalemia in the medical literature [4]. Severe hyperkalemia as a complication of timolol, a topically applied beta-blocker, has also been reported [2]. The duration of hyperkalemia can be fairly prolonged with advanced chronic kidney disease, particularly when renally cleared beta-blockers such as atenolol, are administered [2].
In addition to discontinuing medications that can increase potassium and removal of dietary sources of potassium intake, available treatments for hyperkalemia include intravenous calcium to ameliorate cardiac toxicity if present, intravenous insulin, glucose, nebulized beta-adrenergic agonist, oral gastrointestinal cation exchangers, loop diuretics, and emergency hemodialysis as a last resort for patients with severe renal impairment or for patients with potentially lethal hyperkalemia not responding to conservative measures [8].
This patient is reported to be compliant with hemodialysis. There was no significant modification of his diet over the past years as per the patient. This is his fourth presentation with hyperkalemia, the last two times also assumed to be provoked by the reintroduction of atenolol when studied retrospectively. Every time upon discharge, he was always lost to follow up and presented with a similar problem. Upon looking back into his past records, atenolol was discontinued every time, and he was explained the reason, but it was again prescribed by different doctors a few days before his presentation to the ED. Upon discharge this time, his dedicated primary care physician was contacted and explained the situation, and the patient was also counseled to follow up with a particular primary care physician for comprehensive care.
Because of the absence of any documented underlying cardiac disease and the correlation of recent reintroduction of beta-blocker, we would like to propose that type II second degree heart block was caused by atenolol-induced hyperkalemia. Albeit atenolol can cause heart block as well; AV block is commonly related to drugs but rarely caused by drugs [9].
Conclusions
Even though ESRD patients are already very susceptible to hyperkalemia, in our patient who is compliant to hemodialysis, we should also look into other possible causes of this electrolyte disturbance. Beta-blockers are commonly used for the treatment of hypertension. Physicians should be aware of the medications that can precipitate hyperkalemia, patient characteristics with a higher risk of hyperkalemia, the range of dysrhythmias attributed to hyperkalemia, and implementing treatments without waiting for lab results if necessary.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33692921 | 19,066,921 | 2021-02-05 |
What was the outcome of reaction 'Hyperkalaemia'? | A Case of Reversible Atrioventricular Block Potentially Associated with Atenolol-Induced Hyperkalemia.
Potassium is an extracellular ion that plays an important role in the electrophysiological function of the heart. Any change in the extracellular concentration of potassium can have a marked impression upon cardiac electrophysiology. Underlying kidney disease, certain medical conditions, dietary indiscretions, and medications can precipitate hyperkalemia. Drug-induced hyperkalemia is one of the most important causes of increased serum potassium in everyday clinical practice. Hyperkalemia can lead to various life-threatening dysrhythmias and if left untreated, it will ultimately cause ventricular arrhythmias and asystole. This case report describes an end-stage renal disease (ESRD) patient taking atenolol who presented with hyperkalemia and type II second degree atrioventricular (AV) block. He presented with hyperkalemia when atenolol was introduced and normalized when atenolol was discontinued. The heart block completely resolved after treatment of hyperkalemia.
Introduction
Hyperkalemia is a potentially life-threatening condition that is defined as a serum potassium level above a reference range, usually greater than 5.0 mEq/L; severe hyperkalemia is often defined as a level greater than 6.0 mEq/L. Prescribed medications, over-the-counter drugs, and nutritional supplements that can affect the potassium levels are used by many patients. Although most of these products are well tolerated, drug-induced hyperkalemia may develop in patients with underlying renal impairment or other abnormalities in potassium handling [1]. In hospitalized patients, the incidence of hyperkalemia ranges from 1.3% to 10%, with a mortality rate of 1 per 1,000 patients [2]. Drug-induced hyperkalemia is one of the most important causes in everyday clinical practice and has been identified as a primary contributing factor of hyperkalemia in 35%-75% of hospitalized patients [2]. Beta-blockers are postulated to induce hyperkalemia by suppressing catecholamine stimulated renin release, decrease aldosterone levels and impair cellular uptake of potassium [3]. Beta-blocker can increase serum potassium level by 1 mmol/L or more in end-stage renal disease (ESRD) [2]. Hyperkalemia is more commonly seen with nonselective rather than with cardio-selective beta-blockers [2]. However, there is one reported case of atenolol-induced hyperkalemia in the medical literature [4]. The duration of hyperkalemia can be fairly prolonged with advanced chronic kidney disease, particularly when renally cleared beta-blockers such as atenolol, are administered [2].
There is one reported case of complete heart block induced by hyperkalemia in an ESRD patient that completely resolved to normal with hyperkalemia treatment but months later developed permanent right bundle branch block (RBBB) and left anterior fascicular block [5]. The uniqueness of our case is that although there can be various ranges of heart block induced by hyperkalemia, there is no reported case so far presenting with reversible atrioventricular (AV) block potentially associated with atenolol-induced hyperkalemia in a patient without documented heart disease.
Case presentation
A 64-year-old Asian male with a past medical history of hypertension, type 2 diabetes mellitus, anemia, and ESRD on hemodialysis was referred by the dialysis center for evaluation after the patient was found to have a heart rate in the 30s and was brought to the emergency department (ED) by ambulance. He receives hemodialysis at an outpatient dialysis center three days a week, reported to be compliant, and did not miss any session. However, when he went to the dialysis center, he was found to have low blood pressure (BP) of 88/47 mmHg and a heart rate (HR) of 45 bpm. Leg elevation and inhalational oxygen via nasal cannula were provided but vitals rechecked after 30 minutes revealed BP 145/68 mmHg and HR 36/min. Therefore, emergency medical services (EMS) was activated, and the patient was brought to the ED.
Vitals on triage in the ED were notable for BP 108/54 mmHg, HR 33 bpm, oxygen saturation 100% on 2 liters nasal cannula (NC). He was alert, awake, and answered questions appropriately. He was not aware of his slow heart rate, but he complained of feeling dizzy on and off over the past two days. He denied chest pain, palpitation, shortness of breath, and spells of blackout. Stat EKG was done which showed ventricular rate of 37 bpm, PR interval 284 ms, QRS duration of 154 ms, QTc 466 ms. Fingerstick blood glucose was 195 mg/dl. Further interpretation of EKG revealed second degree 2:1 AV conduction with wide QRS suggestive of type II second degree AV heart block and peaked T wake (Figure 1). This is not his first-time presentation with a similar picture. His past medical records showed that he was admitted three times over the past two years with a similar presentation of hyperkalemia and heart block, one time with first degree AV block, another two times with type I second degree AV block, all resolved to normal sinus rhythm after potassium was normalized. His medications list was significant for atenolol which was discontinued in his previous admissions but was again prescribed a few days before his presentation to the ED.
Figure 1 EKG changes before treatment
His physical examination was unremarkable except for severe bradycardia and cool and clammy extremities. On the cardiac monitor, his heart rate was ranging between 30 bpm to 35 bpm. In view of his previous presentations and EKG findings, he was given calcium gluconate 1 gram slow intravenous (IV) stat, 10 units of IV regular insulin, 25 grams of dextrose 50%, and 12 milliliters of albuterol nebulizer while waiting for blood tests results.
While receiving treatment, basic labs including plasma potassium were sent. The results came back with serum potassium of 8.7 mmol/L, plasma potassium of 8.6 mmol/L. Other chemistries were sodium 135 mmol/L, chloride 96 mmol/L, bicarbonate 23 mmol/L, blood urea nitrogen (BUN) 78 mg/dl, creatinine 14.54 mg/dl, glucose 192 mg/dl, magnesium 2.6 mg/dl, and phosphorous 7.3 mg/dl.
His heart rate showed slight improvement after receiving treatment. Nephrology team recommended emergency hemodialysis. He was also given 30 grams of Kayexylate orally, an additional 2 grams of calcium gluconate slow IV while awaiting hemodialysis set up. He received a total of four hours of hemodialysis with 1K bath for the first 2.5 hours followed by 2K bath for the remaining treatment. Two hours post-dialysis, potassium came back 3.3 mmol/L.
The patient was admitted to the telemetry unit with nephrology on board. His hyperkalemia was thought to be secondary to atenolol considering his multiple presentations provoked by the reintroduction of atenolol. His cardiac enzyme was not elevated. Continuous cardiac monitoring was uneventful. At the time of discharge, his potassium level was 4.6 mmol/L. Beta-blocker was held throughout his hospital stay and also not continued upon discharge. His EKG on the day of his discharge demonstrated complete resolution of the previously seen type II second degree AV block pattern. EKG showed a rate of 72 bpm, PR interval 156 ms, normal sinus rhythm, and slightly prolonged QTc 462 ms (Figure 2).
Figure 2 Normal sinus rhythm after treatment
Discussion
This case depicts an unusual presentation of atenolol-induced hyperkalemia causing type II second degree heart block that resolves completely to normal after correction of hyperkalemia, and discontinuation of atenolol. In this patient, who is reported to have started taking atenolol a few days before presentation, it is reasonable to believe that his hyperkalemia could be induced by atenolol, and heart block could be contributed by atenolol-induced hyperkalemia. For some reason, even though atenolol was discontinued upon previous discharges because of similar presentation, it was again prescribed by different doctors. Contributing factors could be lost to follow up upon discharge, no dedicated primary doctor, language barrier to some extent even though language line was properly used, and lack of health knowledge. In view of his recurrent presentation of hyperkalemia-induced heart block, electrophysiologic studies would be warranted to rule out any underlying pathology. However, the disappearance of hyperkalemia-induced heart block with hyperkalemia treatment and discontinuation of atenolol, the absence of any other acute causes of AV block make it seem unlikely. The resolution of type II second degree heart block to sinus rhythm after treatment of hyperkalemia and hemodialysis also suggest that atenolol-induced hyperkalemia is responsible for this high-grade AV block.
Hyperkalemia can lower cell-resting action potential and causes abnormal heart muscle function resulting in EKG findings initially with tall and tented T wave, loss of P wave, prolong PR interval, widened QRS complex, and eventually sine wave before the heart stops [6]. Varying degrees of heart block can also happen with this electrolyte disturbance but advanced heart blocks such as second- and third-degree AV blocks are generally found only in patients with underlying heart disease, heart failures, or preexisting conduction abnormalities. It was reasoned that underlying coronary artery or diffuse cardiac disease have already destroyed the AV node and His-Purkinje system to a certain extent that hyperkalemia can aggravate pre-existing diagnosed or undiagnosed conduction defects [7].
Beta-blocker can increase serum potassium level by 1 mmol/L or more in ESRD [2]. Hyperkalemia was mainly seen with nonselective rather than with cardio-selective beta-blockers [2]. However, there is one reported case of atenolol-induced hyperkalemia in the medical literature [4]. Severe hyperkalemia as a complication of timolol, a topically applied beta-blocker, has also been reported [2]. The duration of hyperkalemia can be fairly prolonged with advanced chronic kidney disease, particularly when renally cleared beta-blockers such as atenolol, are administered [2].
In addition to discontinuing medications that can increase potassium and removal of dietary sources of potassium intake, available treatments for hyperkalemia include intravenous calcium to ameliorate cardiac toxicity if present, intravenous insulin, glucose, nebulized beta-adrenergic agonist, oral gastrointestinal cation exchangers, loop diuretics, and emergency hemodialysis as a last resort for patients with severe renal impairment or for patients with potentially lethal hyperkalemia not responding to conservative measures [8].
This patient is reported to be compliant with hemodialysis. There was no significant modification of his diet over the past years as per the patient. This is his fourth presentation with hyperkalemia, the last two times also assumed to be provoked by the reintroduction of atenolol when studied retrospectively. Every time upon discharge, he was always lost to follow up and presented with a similar problem. Upon looking back into his past records, atenolol was discontinued every time, and he was explained the reason, but it was again prescribed by different doctors a few days before his presentation to the ED. Upon discharge this time, his dedicated primary care physician was contacted and explained the situation, and the patient was also counseled to follow up with a particular primary care physician for comprehensive care.
Because of the absence of any documented underlying cardiac disease and the correlation of recent reintroduction of beta-blocker, we would like to propose that type II second degree heart block was caused by atenolol-induced hyperkalemia. Albeit atenolol can cause heart block as well; AV block is commonly related to drugs but rarely caused by drugs [9].
Conclusions
Even though ESRD patients are already very susceptible to hyperkalemia, in our patient who is compliant to hemodialysis, we should also look into other possible causes of this electrolyte disturbance. Beta-blockers are commonly used for the treatment of hypertension. Physicians should be aware of the medications that can precipitate hyperkalemia, patient characteristics with a higher risk of hyperkalemia, the range of dysrhythmias attributed to hyperkalemia, and implementing treatments without waiting for lab results if necessary.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33692921 | 19,066,921 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ventricular fibrillation'. | Ventricular Fibrillation: Potential Deadly Consequence of Discontinuation of Methimazole Prior to Radioiodine Ablation.
The following case involves a 62-year-old female patient suffering from heart failure with reduced ejection fraction (HFrEF) secondary to non-ischemic cardiomyopathy and Graves disease, who developed ventricular fibrillation (VF) after discontinuation of methimazole in preparation for radioiodine ablation. Electrocardiogram (ECG) showed a severely prolonged QTc in the setting of thyrotoxicosis, which significantly improved with high dose methimazole. VF secondary to thyrotoxicosis has rarely been reported and the literature review shows scarce data on its mechanism. Our case demonstrates not only a possible mechanism for the arrhythmia, but also highlights a potential risk factor for it. The report details how discontinuing antithyroid medication leads to VF in our patient and reviews the current literature on antithyroid withdrawal prior to radioiodine ablation therapy. Caution should be taken when discontinuing antithyroid medications in patients with advanced heart failure as potentially lethal ventricular arrhythmias can ensue.
Introduction
Hyperthyroidism imposes various cardiovascular complications and hemodynamic changes like increased contractility, increased preload, and decreased systemic vascular resistance, which all result in increased cardiac output [1,2]. The most common cardiac complication is atrial fibrillation which occurs in approximately 15% of overtly hyperthyroid patients [3]. The occurrence of dangerous arrhythmias such as ventricular fibrillation (VF), although rare, can cause sudden cardiac death [4]. Malignant ventricular arrhythmias secondary to QT prolongation from thyrotoxicosis are seldom encountered in the inpatient setting. Factors that contribute to a fatal arrhythmia are thyrotoxicosis in the setting of an already weakened heart, seen in our patient. Literature review shows that ventricle repolarization is greatly affected in hyperthyroidism [3-5]. Ventricular repolarization is assessed using the QT interval corrected for the heart rate (QTc) on an electrocardiogram (ECG). Research shows a significant positive correlation between QTc and thyroid hormones, especially free T4 levels. However, the mechanism and pathophysiology are not well understood [4-8]. The correlation has even been reported in patients with subclinical hyperthyroidism [7]. Prolonged QTc is associated with an increased risk for lethal arrhythmias such as torsade de Pointes (TdP) or VF. Thyrotoxicosis from antithyroid withdrawal for radioiodine ablation has been reported, however, serious adverse events such as VF have rarely been reported. This case shows after five days of discontinuing methimazole, the QTc increased to dangerous levels, triggering VF in our patient. Various withdrawal periods have been reported: current guidelines dictate that antithyroid medications should be held for three to seven days prior to radioiodine ablation in order to maximize radioiodine uptake [9-13]. However, the literature does not specify the duration of treatment suspension when it relates to individuals with cardiac comorbidities such as advanced heart failure. Five days without methimazole lead to a QTc of 607 ms, which resulted in VF in our patient. Thus, in patients with preexisting heart failure, discontinuation of antithyroid medication should be followed up with careful QTc monitoring prior to radioiodine ablation therapy.
Case presentation
The patient is a 62-year-old female with heart failure with reduced ejection fraction (HFrEF) from nonischemic cardiomyopathy (ejection fraction of 25%), automatic implantable cardioverter-defibrillator (AICD), hypertension, and Graves’ disease who presented after an episode of syncope at home. The patient stated that she was standing by her dresser when she suddenly started having palpitations, diaphoresis, and nausea. After that, she lost consciousness for a few seconds and fell to the floor (no head trauma). She denied any prodromal dizziness, light-headedness, or vertigo. The patient was diagnosed with Graves’ disease nine months prior to presentation. The patient stated that she was instructed by her endocrinologist to discontinue her methimazole for one week as she was scheduled to undergo elective radioiodine ablation of the thyroid. A recent thyroid uptake study showed 83% homogeneous uptake in the thyroid, consistent with graves thyrotoxicosis. The patient presented to the hospital five days after discontinuing her methimazole. She also reported palpitations, poor appetite, feeling anxious, and fatigue since stopping her medication. Home medications included aspirin 81 mg daily, metoprolol succinate ER 25 mg daily, sacubitril/valsartan 24/26 mg twice daily, spironolactone 25 mg daily, furosemide 40 mg daily, and methimazole 20 mg daily. The patient denied any past surgical history except for AICD placement. Social and family histories were significant only for Graves' disease in biological mother.
On admission, patient vitals were a pulse of 90 (regular), blood pressure of 104/58, respiratory rate of 18, and oxygen saturation of 100% on room air. Physical examination was unremarkable. Patients labs were significant for TSH of less than 0.005 (reference range 0.270-4.200 mcIU/mL), free T3 of 21.3 (reference range 0.20-4.40 pg/mL), and free T4 of greater than 7.77 (reference range 0.90-1.71 ng/dL). chest X-ray was negative for acute pathology. Initial ECG showed nonspecific intraventricular conduction delay and severe QTc prolongation of 607 ms (Figure 1). Medical record review showed patient recently followed up with a primary care physician who obtained thyroid studies and ECG. The patient’s QTc interval three weeks prior to admission was 437 (Figure 2). Thyroid function testing showed TSH of less than 0.005, free T4 of 4.7, and free T3 of 8.80. During her visit, methimazole was increased from 10 mg daily to 20 mg daily. Thus, the patient’s QTc increased from 437 ms to 607 ms (Figures 1 and 2) after discontinuing methimazole for five days. AICD interrogation revealed the patient had an episode of VF (same time as syncope occurred) and received an appropriate shock (Figure 3). AICD also showed frequent premature ventricular contractions (PVCs) prior to VF (Figure 4). Although not apparent on our patient’s AICD interrogation, the PVCs could have fallen on a T-wave from a previous contraction enabling the “R-on-T” phenomenon, which possibly triggered her VF [14]. The patient was found to have frequent PVCs on both AICD and in-hospital ECGs (Figures 1 and 4). Patient’s magnesium on admission was 2.1 (reference range 1.7-2.6 mg/dL) and potassium was 3.9 (reference range 3.5-5.1 mmol/L). Troponin and Pro-BNP were within normal limits. Transthoracic echocardiogram (TTE) showed a stable ejection fraction of 25%, no acute wall motion abnormalities, and no new structural pathologies when compared to the previous TTE done six months ago. Therefore, the likelihood of an electrolyte abnormality, myocardial ischemia or infarct, or new structural abnormality as the cause of VF was less likely. Further record review traced the patient’s diagnosis of hyperthyroidism to nine months ago, where she had a QTc of 397 (Figure 2). Thyroid studies showed TSH <0.005, free T4 of 2.08, and normal free T3 at 4.05.
Figure 1 QTc Improvement With Methimazole Treatment
Image shows improving QTc interval after treatment with high-dose methimazole (30 mg every 6 hours). After >24 hours of treatment, QTc interval improved from 607 to 431 and after >48 hours of treatment QTc improved to 399. QTc: corrected QT interval for heart rate.
Figure 2 Relationship Between QTc and Free T4
Image shows a positive correlation between QTc interval and the patient’s free thyroxine (T4). In March 2019, free T4 was 2.08 and QTc was 297 ms. In November 2019, free T4 increased to 4.70 and QTc increased to 437 ms.
Figure 3 Ventricular Fibrillation on AICD Interrogation
AICD interrogation revealed VF, which can be seen on the ventricular electrogram (V) on the AICD (black box). The onset of the VF is labeled with the blue arrow and the red arrow signifies the 40-Joule defibrillation shock, which converted the patient to sinus rhythm. VF: ventricular fibrillation; FF: far-field electrogram; AV: marker channel; V: ventricular electrogram; A: atrial electrogram; AICD: automatic implantable cardioverter-defibrillators.
Figure 4 PVCs Prior to Ventricular Fibrillation: R-on-T Phenomena
AICD detected PVCs prior to VF. PVCs (red arrows) can be seen on the ventricular electrogram (V). These PVCs supports the assumption that along with QTc prolongation, the PVCs could have resulted in the “R on T” phenomena, which triggered the VF. FF: far-field electrogram; AV: marker channel; V: ventricular electrogram; A: atrial electrogram; PVC: premature ventricular contraction.
Endocrinology was consulted and recommended the initiation of methimazole at a dose of 30 mg every six hours. EP Cardiology also recommended the initiation of antithyroid medication, avoidance of QT-prolonging drugs, maintenance of potassium above 4 and magnesium above 2, and serial ECG for QTc monitor. On day 2 of admission, and after receiving a high dose of methimazole for 24 hours (onset of action 12-16 hours), repeat ECG showed QTc of 431 (Figure 1). On day 3 of admission, QTc was 399 (Figure 1). The patient was discharged home on 30 mg methimazole twice daily with instructions to follow up with her endocrinologist and cardiologist within one week. A follow-up with the patient revealed that radioiodine ablation was postponed until the patient became euthyroid; discussion regarding potential lifelong antithyroid medication instead of ablation was being considered. Post-discharge AICD interrogation did not reveal any further ventricular arrhythmias.
Discussion
Thyroid hormone whether in its absence or excess seems to be able to cause QTc prolongation. The mechanism by which both hypothyroidism and hyperthyroidism can cause ventricular repolarization delay/OTc prolongation is not well understood. Literature review shows that in the case of hypothyroidism, there could be a combination of disturbances leading to QTc prolongation. Studies show that in hypothyroidism, there is an alteration of autonomic modulation of the heart leading to sympathovagal imbalance and an increased inhomogeneity of ventricular recovery times [8,15,16]. Furthermore, in a study conducted on guinea pigs, there was a decrease in the slow component of delayed rectifier K current (IKs), believed to be a major factor in disrupting ventricular repolarization [16,17].
Numerous studies have shown a strong association between hyperthyroidism and QTc prolongation. A positive correlation between free T4 and the degree of QT prolongation was seen; patients with higher levels of free T4 had longer QTc duration [1,3-8]. This positive correlation was present with our patient: as free T4 increased, QTc also increased (Table 1). Normalization of free T4 leads and achievement of the euthyroid state has been shown to normalize QTc duration in hyperthyroid patients [4]. Although repeat-free T4 was not done in our patient after high dose methimazole treatment, serial QTc did show significant and continued improvement (Figure 1 and Table 1). The pathophysiology of QTc prolongation due to a hyperthyroid state is not well understood. A few studies and proposed theories have explained the possible mechanism by which thyroid hormone increases ventricle repolarization and thus QTc. One theory focuses on the effect of thyroid hormone on the cardiac myocyte Na/K1 ATPase receptor. It is proposed that increased activity in this receptor secondary to the action of T4 leads to increased intracellular potassium, resulting in membrane hyperpolarization and higher QTc interval [4,5,8]. A separate study done on rats showed increased gene expression of the Na/K1 ATPase receptor after transplanted hearts were treated with T4 [4]. These findings suggest that there is a possible dose-dependent effect of T4 on the intracellular potassium of cardiac myocytes and, in turn, ventricle repolarization manifests as prolonged QTc [4]. Although very rare, new-onset thyrotoxicosis can precipitate VF theoretically by inducing coronary vasospasm leading to myocardial ischemia [1]. However, no evidence of ischemia was noted in our patient as she did not complain of angina; cardiac enzymes were within normal limits throughout admission; ECG did not show evidence of ischemia; TTE was negative for acute wall motion abnormality.
Patients with HFrEF and Graves' disease are at higher risk for cardiac arrhythmias than patients without heart failure. Maladaptive hypertrophic and fibrotic myocardial remodeling in advanced heart failure can predispose a patient to a spectrum of ventricular arrhythmias [1]. Discontinuation of medications such as methimazole in a patient with advanced heart failure can further increase the risk for ventricular arrhythmias. Our patient was instructed to discontinue medications in order to decrease the risk of radioiodine ablation failure. A meta-analysis of 14 randomized controlled trials with a total of 1306 participants showed that the continuation of antithyroid drugs in the week prior to radioiodine ablation increased the rate of ablation failure [13]. The efficacy of radioiodine therapy was reduced when the antithyroid medication was continued during ablation. Research shows that not only did radioiodine have a lower uptake and shorter half-life, but also there was a varied distribution of the radioiodine throughout the thyroid [12].
The minimum duration for withdrawal of treatment, prior to radioiodine ablation, has not been clearly established. The World Journal of Nuclear Medicine and the Society of Nuclear Medicine recommend three-day withdrawal as it has been shown to be effective in treating Graves’ disease without exacerbating hyperthyroidism. Yet, controlled clinical trials and comparative studies show that a two-day withdrawal is sufficient to restore the efficacy of radioiodine for thyroid ablation [9-12]. In the comparative study, patients in a two-day antithyroid withdrawal regimen were examined prospectively using radioiodine uptake, serum-free T4, and an outcome of therapy. These parameters were compared to those in a seven-day withdrawal regimen retrospectively. The results showed no statistically significant difference in radioiodine uptake in the two-day withdrawal group compared to the seven-day withdrawal group. The mean serum-free T4 measured 24 hours after radioiodine therapy revealed that the seven-day group had significantly higher levels than the two-day group. Thus, this study shows that the two-day withdrawal period had similar results for uptake and did not exacerbate hyperthyroidism when compared to the seven-day withdrawal period [10]. In the controlled clinical trial, radioiodine kinetics was studied under continued thiamazole medication and after discontinuation for one to two days in 316 patients. The results showed that when the antithyroid medication was discontinued for at least two days, radioiodine uptake was near normal; however, uptake within one day of discontinuation was reduced. Patients in the continued thiamazole medication group showed a decreased uptake by a factor of 2.5 [12].
A two-day withdrawal period may be useful for high-risk patients with cardiac comorbidities such as advanced heart failure. In our patient, discontinuation of methimazole for two days instead of seven days could have prevented thyrotoxicosis and in turn VF from QTc prolongation. It is evident from our patient's ECGs that serum T4 levels had a positive correlation with QTc interval (Table 1). Severely elevated T4 can lead to dangerously prolonged QTc resulting in ventricular arrhythmias such as VF or TdP. The risk of prolongation of QTc is likely further increased in our patient given her advanced heart failure. Withdrawal of treatment should be minimized and if indicated to the least number of days. QTc should be monitored frequently when the withdrawal is indicated, especially regarding patients with cardiac comorbidities. Further research and concrete guidelines for the duration of withdrawal of antithyroid medication prior to radioiodine ablation in high-risk patients is needed.
Table 1 Positive Correlation Between Correct QT Interval and Free Thyroxine
The table shows a positive correlation between QTc and free T4 levels in our patient. As free T4 levels increased the QTc of our patient also increased. The QTc interval dramatically decreased from 607 ms to 431 ms after receiving >24 hours of high dose methimazole (30 mg every six hours). Free T4 was not checked after initial testing during the December 2020 admission. Corrected QT interval (QTc) is in milliseconds; free thyroxine level (T4) is in nanograms per deciliter.
March 2019 November 2019 December 2020: Day 1 December 2020: Day 2 December 2020: Day 3
Corrected QT interval 397 437 607 431 399
Free thyroxine level 2.08 4.7 >7.77 Not checked Not checked
Conclusions
In this case, the patient’s syncopal episode due to VF may have been due to severe QT prolongation in the setting of thyrotoxicosis from medication withdrawal. Given her history of nonischemic cardiomyopathy with an ejection fraction of 25%, the risk for ventricular arrhythmias is already elevated. Caution should be taken when withdrawing antithyroid medication in patients with advanced heart failure as the risks for severe QTc prolongation and subsequent malignant ventricular arrhythmias may be increased. If a withdrawal is indicated, the least amount of duration should be chosen and frequent monitoring of QTc should be performed.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | ASPIRIN, FUROSEMIDE, METHIMAZOLE, METOPROLOL SUCCINATE, SACUBITRIL\VALSARTAN, SPIRONOLACTONE | DrugsGivenReaction | CC BY | 33692927 | 19,062,069 | 2021-02-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Withdrawal syndrome'. | Ventricular Fibrillation: Potential Deadly Consequence of Discontinuation of Methimazole Prior to Radioiodine Ablation.
The following case involves a 62-year-old female patient suffering from heart failure with reduced ejection fraction (HFrEF) secondary to non-ischemic cardiomyopathy and Graves disease, who developed ventricular fibrillation (VF) after discontinuation of methimazole in preparation for radioiodine ablation. Electrocardiogram (ECG) showed a severely prolonged QTc in the setting of thyrotoxicosis, which significantly improved with high dose methimazole. VF secondary to thyrotoxicosis has rarely been reported and the literature review shows scarce data on its mechanism. Our case demonstrates not only a possible mechanism for the arrhythmia, but also highlights a potential risk factor for it. The report details how discontinuing antithyroid medication leads to VF in our patient and reviews the current literature on antithyroid withdrawal prior to radioiodine ablation therapy. Caution should be taken when discontinuing antithyroid medications in patients with advanced heart failure as potentially lethal ventricular arrhythmias can ensue.
Introduction
Hyperthyroidism imposes various cardiovascular complications and hemodynamic changes like increased contractility, increased preload, and decreased systemic vascular resistance, which all result in increased cardiac output [1,2]. The most common cardiac complication is atrial fibrillation which occurs in approximately 15% of overtly hyperthyroid patients [3]. The occurrence of dangerous arrhythmias such as ventricular fibrillation (VF), although rare, can cause sudden cardiac death [4]. Malignant ventricular arrhythmias secondary to QT prolongation from thyrotoxicosis are seldom encountered in the inpatient setting. Factors that contribute to a fatal arrhythmia are thyrotoxicosis in the setting of an already weakened heart, seen in our patient. Literature review shows that ventricle repolarization is greatly affected in hyperthyroidism [3-5]. Ventricular repolarization is assessed using the QT interval corrected for the heart rate (QTc) on an electrocardiogram (ECG). Research shows a significant positive correlation between QTc and thyroid hormones, especially free T4 levels. However, the mechanism and pathophysiology are not well understood [4-8]. The correlation has even been reported in patients with subclinical hyperthyroidism [7]. Prolonged QTc is associated with an increased risk for lethal arrhythmias such as torsade de Pointes (TdP) or VF. Thyrotoxicosis from antithyroid withdrawal for radioiodine ablation has been reported, however, serious adverse events such as VF have rarely been reported. This case shows after five days of discontinuing methimazole, the QTc increased to dangerous levels, triggering VF in our patient. Various withdrawal periods have been reported: current guidelines dictate that antithyroid medications should be held for three to seven days prior to radioiodine ablation in order to maximize radioiodine uptake [9-13]. However, the literature does not specify the duration of treatment suspension when it relates to individuals with cardiac comorbidities such as advanced heart failure. Five days without methimazole lead to a QTc of 607 ms, which resulted in VF in our patient. Thus, in patients with preexisting heart failure, discontinuation of antithyroid medication should be followed up with careful QTc monitoring prior to radioiodine ablation therapy.
Case presentation
The patient is a 62-year-old female with heart failure with reduced ejection fraction (HFrEF) from nonischemic cardiomyopathy (ejection fraction of 25%), automatic implantable cardioverter-defibrillator (AICD), hypertension, and Graves’ disease who presented after an episode of syncope at home. The patient stated that she was standing by her dresser when she suddenly started having palpitations, diaphoresis, and nausea. After that, she lost consciousness for a few seconds and fell to the floor (no head trauma). She denied any prodromal dizziness, light-headedness, or vertigo. The patient was diagnosed with Graves’ disease nine months prior to presentation. The patient stated that she was instructed by her endocrinologist to discontinue her methimazole for one week as she was scheduled to undergo elective radioiodine ablation of the thyroid. A recent thyroid uptake study showed 83% homogeneous uptake in the thyroid, consistent with graves thyrotoxicosis. The patient presented to the hospital five days after discontinuing her methimazole. She also reported palpitations, poor appetite, feeling anxious, and fatigue since stopping her medication. Home medications included aspirin 81 mg daily, metoprolol succinate ER 25 mg daily, sacubitril/valsartan 24/26 mg twice daily, spironolactone 25 mg daily, furosemide 40 mg daily, and methimazole 20 mg daily. The patient denied any past surgical history except for AICD placement. Social and family histories were significant only for Graves' disease in biological mother.
On admission, patient vitals were a pulse of 90 (regular), blood pressure of 104/58, respiratory rate of 18, and oxygen saturation of 100% on room air. Physical examination was unremarkable. Patients labs were significant for TSH of less than 0.005 (reference range 0.270-4.200 mcIU/mL), free T3 of 21.3 (reference range 0.20-4.40 pg/mL), and free T4 of greater than 7.77 (reference range 0.90-1.71 ng/dL). chest X-ray was negative for acute pathology. Initial ECG showed nonspecific intraventricular conduction delay and severe QTc prolongation of 607 ms (Figure 1). Medical record review showed patient recently followed up with a primary care physician who obtained thyroid studies and ECG. The patient’s QTc interval three weeks prior to admission was 437 (Figure 2). Thyroid function testing showed TSH of less than 0.005, free T4 of 4.7, and free T3 of 8.80. During her visit, methimazole was increased from 10 mg daily to 20 mg daily. Thus, the patient’s QTc increased from 437 ms to 607 ms (Figures 1 and 2) after discontinuing methimazole for five days. AICD interrogation revealed the patient had an episode of VF (same time as syncope occurred) and received an appropriate shock (Figure 3). AICD also showed frequent premature ventricular contractions (PVCs) prior to VF (Figure 4). Although not apparent on our patient’s AICD interrogation, the PVCs could have fallen on a T-wave from a previous contraction enabling the “R-on-T” phenomenon, which possibly triggered her VF [14]. The patient was found to have frequent PVCs on both AICD and in-hospital ECGs (Figures 1 and 4). Patient’s magnesium on admission was 2.1 (reference range 1.7-2.6 mg/dL) and potassium was 3.9 (reference range 3.5-5.1 mmol/L). Troponin and Pro-BNP were within normal limits. Transthoracic echocardiogram (TTE) showed a stable ejection fraction of 25%, no acute wall motion abnormalities, and no new structural pathologies when compared to the previous TTE done six months ago. Therefore, the likelihood of an electrolyte abnormality, myocardial ischemia or infarct, or new structural abnormality as the cause of VF was less likely. Further record review traced the patient’s diagnosis of hyperthyroidism to nine months ago, where she had a QTc of 397 (Figure 2). Thyroid studies showed TSH <0.005, free T4 of 2.08, and normal free T3 at 4.05.
Figure 1 QTc Improvement With Methimazole Treatment
Image shows improving QTc interval after treatment with high-dose methimazole (30 mg every 6 hours). After >24 hours of treatment, QTc interval improved from 607 to 431 and after >48 hours of treatment QTc improved to 399. QTc: corrected QT interval for heart rate.
Figure 2 Relationship Between QTc and Free T4
Image shows a positive correlation between QTc interval and the patient’s free thyroxine (T4). In March 2019, free T4 was 2.08 and QTc was 297 ms. In November 2019, free T4 increased to 4.70 and QTc increased to 437 ms.
Figure 3 Ventricular Fibrillation on AICD Interrogation
AICD interrogation revealed VF, which can be seen on the ventricular electrogram (V) on the AICD (black box). The onset of the VF is labeled with the blue arrow and the red arrow signifies the 40-Joule defibrillation shock, which converted the patient to sinus rhythm. VF: ventricular fibrillation; FF: far-field electrogram; AV: marker channel; V: ventricular electrogram; A: atrial electrogram; AICD: automatic implantable cardioverter-defibrillators.
Figure 4 PVCs Prior to Ventricular Fibrillation: R-on-T Phenomena
AICD detected PVCs prior to VF. PVCs (red arrows) can be seen on the ventricular electrogram (V). These PVCs supports the assumption that along with QTc prolongation, the PVCs could have resulted in the “R on T” phenomena, which triggered the VF. FF: far-field electrogram; AV: marker channel; V: ventricular electrogram; A: atrial electrogram; PVC: premature ventricular contraction.
Endocrinology was consulted and recommended the initiation of methimazole at a dose of 30 mg every six hours. EP Cardiology also recommended the initiation of antithyroid medication, avoidance of QT-prolonging drugs, maintenance of potassium above 4 and magnesium above 2, and serial ECG for QTc monitor. On day 2 of admission, and after receiving a high dose of methimazole for 24 hours (onset of action 12-16 hours), repeat ECG showed QTc of 431 (Figure 1). On day 3 of admission, QTc was 399 (Figure 1). The patient was discharged home on 30 mg methimazole twice daily with instructions to follow up with her endocrinologist and cardiologist within one week. A follow-up with the patient revealed that radioiodine ablation was postponed until the patient became euthyroid; discussion regarding potential lifelong antithyroid medication instead of ablation was being considered. Post-discharge AICD interrogation did not reveal any further ventricular arrhythmias.
Discussion
Thyroid hormone whether in its absence or excess seems to be able to cause QTc prolongation. The mechanism by which both hypothyroidism and hyperthyroidism can cause ventricular repolarization delay/OTc prolongation is not well understood. Literature review shows that in the case of hypothyroidism, there could be a combination of disturbances leading to QTc prolongation. Studies show that in hypothyroidism, there is an alteration of autonomic modulation of the heart leading to sympathovagal imbalance and an increased inhomogeneity of ventricular recovery times [8,15,16]. Furthermore, in a study conducted on guinea pigs, there was a decrease in the slow component of delayed rectifier K current (IKs), believed to be a major factor in disrupting ventricular repolarization [16,17].
Numerous studies have shown a strong association between hyperthyroidism and QTc prolongation. A positive correlation between free T4 and the degree of QT prolongation was seen; patients with higher levels of free T4 had longer QTc duration [1,3-8]. This positive correlation was present with our patient: as free T4 increased, QTc also increased (Table 1). Normalization of free T4 leads and achievement of the euthyroid state has been shown to normalize QTc duration in hyperthyroid patients [4]. Although repeat-free T4 was not done in our patient after high dose methimazole treatment, serial QTc did show significant and continued improvement (Figure 1 and Table 1). The pathophysiology of QTc prolongation due to a hyperthyroid state is not well understood. A few studies and proposed theories have explained the possible mechanism by which thyroid hormone increases ventricle repolarization and thus QTc. One theory focuses on the effect of thyroid hormone on the cardiac myocyte Na/K1 ATPase receptor. It is proposed that increased activity in this receptor secondary to the action of T4 leads to increased intracellular potassium, resulting in membrane hyperpolarization and higher QTc interval [4,5,8]. A separate study done on rats showed increased gene expression of the Na/K1 ATPase receptor after transplanted hearts were treated with T4 [4]. These findings suggest that there is a possible dose-dependent effect of T4 on the intracellular potassium of cardiac myocytes and, in turn, ventricle repolarization manifests as prolonged QTc [4]. Although very rare, new-onset thyrotoxicosis can precipitate VF theoretically by inducing coronary vasospasm leading to myocardial ischemia [1]. However, no evidence of ischemia was noted in our patient as she did not complain of angina; cardiac enzymes were within normal limits throughout admission; ECG did not show evidence of ischemia; TTE was negative for acute wall motion abnormality.
Patients with HFrEF and Graves' disease are at higher risk for cardiac arrhythmias than patients without heart failure. Maladaptive hypertrophic and fibrotic myocardial remodeling in advanced heart failure can predispose a patient to a spectrum of ventricular arrhythmias [1]. Discontinuation of medications such as methimazole in a patient with advanced heart failure can further increase the risk for ventricular arrhythmias. Our patient was instructed to discontinue medications in order to decrease the risk of radioiodine ablation failure. A meta-analysis of 14 randomized controlled trials with a total of 1306 participants showed that the continuation of antithyroid drugs in the week prior to radioiodine ablation increased the rate of ablation failure [13]. The efficacy of radioiodine therapy was reduced when the antithyroid medication was continued during ablation. Research shows that not only did radioiodine have a lower uptake and shorter half-life, but also there was a varied distribution of the radioiodine throughout the thyroid [12].
The minimum duration for withdrawal of treatment, prior to radioiodine ablation, has not been clearly established. The World Journal of Nuclear Medicine and the Society of Nuclear Medicine recommend three-day withdrawal as it has been shown to be effective in treating Graves’ disease without exacerbating hyperthyroidism. Yet, controlled clinical trials and comparative studies show that a two-day withdrawal is sufficient to restore the efficacy of radioiodine for thyroid ablation [9-12]. In the comparative study, patients in a two-day antithyroid withdrawal regimen were examined prospectively using radioiodine uptake, serum-free T4, and an outcome of therapy. These parameters were compared to those in a seven-day withdrawal regimen retrospectively. The results showed no statistically significant difference in radioiodine uptake in the two-day withdrawal group compared to the seven-day withdrawal group. The mean serum-free T4 measured 24 hours after radioiodine therapy revealed that the seven-day group had significantly higher levels than the two-day group. Thus, this study shows that the two-day withdrawal period had similar results for uptake and did not exacerbate hyperthyroidism when compared to the seven-day withdrawal period [10]. In the controlled clinical trial, radioiodine kinetics was studied under continued thiamazole medication and after discontinuation for one to two days in 316 patients. The results showed that when the antithyroid medication was discontinued for at least two days, radioiodine uptake was near normal; however, uptake within one day of discontinuation was reduced. Patients in the continued thiamazole medication group showed a decreased uptake by a factor of 2.5 [12].
A two-day withdrawal period may be useful for high-risk patients with cardiac comorbidities such as advanced heart failure. In our patient, discontinuation of methimazole for two days instead of seven days could have prevented thyrotoxicosis and in turn VF from QTc prolongation. It is evident from our patient's ECGs that serum T4 levels had a positive correlation with QTc interval (Table 1). Severely elevated T4 can lead to dangerously prolonged QTc resulting in ventricular arrhythmias such as VF or TdP. The risk of prolongation of QTc is likely further increased in our patient given her advanced heart failure. Withdrawal of treatment should be minimized and if indicated to the least number of days. QTc should be monitored frequently when the withdrawal is indicated, especially regarding patients with cardiac comorbidities. Further research and concrete guidelines for the duration of withdrawal of antithyroid medication prior to radioiodine ablation in high-risk patients is needed.
Table 1 Positive Correlation Between Correct QT Interval and Free Thyroxine
The table shows a positive correlation between QTc and free T4 levels in our patient. As free T4 levels increased the QTc of our patient also increased. The QTc interval dramatically decreased from 607 ms to 431 ms after receiving >24 hours of high dose methimazole (30 mg every six hours). Free T4 was not checked after initial testing during the December 2020 admission. Corrected QT interval (QTc) is in milliseconds; free thyroxine level (T4) is in nanograms per deciliter.
March 2019 November 2019 December 2020: Day 1 December 2020: Day 2 December 2020: Day 3
Corrected QT interval 397 437 607 431 399
Free thyroxine level 2.08 4.7 >7.77 Not checked Not checked
Conclusions
In this case, the patient’s syncopal episode due to VF may have been due to severe QT prolongation in the setting of thyrotoxicosis from medication withdrawal. Given her history of nonischemic cardiomyopathy with an ejection fraction of 25%, the risk for ventricular arrhythmias is already elevated. Caution should be taken when withdrawing antithyroid medication in patients with advanced heart failure as the risks for severe QTc prolongation and subsequent malignant ventricular arrhythmias may be increased. If a withdrawal is indicated, the least amount of duration should be chosen and frequent monitoring of QTc should be performed.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | ASPIRIN, FUROSEMIDE, METHIMAZOLE, METOPROLOL SUCCINATE, SACUBITRIL\VALSARTAN, SPIRONOLACTONE | DrugsGivenReaction | CC BY | 33692927 | 19,062,069 | 2021-02-06 |
What was the dosage of drug 'SACUBITRIL\VALSARTAN'? | Ventricular Fibrillation: Potential Deadly Consequence of Discontinuation of Methimazole Prior to Radioiodine Ablation.
The following case involves a 62-year-old female patient suffering from heart failure with reduced ejection fraction (HFrEF) secondary to non-ischemic cardiomyopathy and Graves disease, who developed ventricular fibrillation (VF) after discontinuation of methimazole in preparation for radioiodine ablation. Electrocardiogram (ECG) showed a severely prolonged QTc in the setting of thyrotoxicosis, which significantly improved with high dose methimazole. VF secondary to thyrotoxicosis has rarely been reported and the literature review shows scarce data on its mechanism. Our case demonstrates not only a possible mechanism for the arrhythmia, but also highlights a potential risk factor for it. The report details how discontinuing antithyroid medication leads to VF in our patient and reviews the current literature on antithyroid withdrawal prior to radioiodine ablation therapy. Caution should be taken when discontinuing antithyroid medications in patients with advanced heart failure as potentially lethal ventricular arrhythmias can ensue.
Introduction
Hyperthyroidism imposes various cardiovascular complications and hemodynamic changes like increased contractility, increased preload, and decreased systemic vascular resistance, which all result in increased cardiac output [1,2]. The most common cardiac complication is atrial fibrillation which occurs in approximately 15% of overtly hyperthyroid patients [3]. The occurrence of dangerous arrhythmias such as ventricular fibrillation (VF), although rare, can cause sudden cardiac death [4]. Malignant ventricular arrhythmias secondary to QT prolongation from thyrotoxicosis are seldom encountered in the inpatient setting. Factors that contribute to a fatal arrhythmia are thyrotoxicosis in the setting of an already weakened heart, seen in our patient. Literature review shows that ventricle repolarization is greatly affected in hyperthyroidism [3-5]. Ventricular repolarization is assessed using the QT interval corrected for the heart rate (QTc) on an electrocardiogram (ECG). Research shows a significant positive correlation between QTc and thyroid hormones, especially free T4 levels. However, the mechanism and pathophysiology are not well understood [4-8]. The correlation has even been reported in patients with subclinical hyperthyroidism [7]. Prolonged QTc is associated with an increased risk for lethal arrhythmias such as torsade de Pointes (TdP) or VF. Thyrotoxicosis from antithyroid withdrawal for radioiodine ablation has been reported, however, serious adverse events such as VF have rarely been reported. This case shows after five days of discontinuing methimazole, the QTc increased to dangerous levels, triggering VF in our patient. Various withdrawal periods have been reported: current guidelines dictate that antithyroid medications should be held for three to seven days prior to radioiodine ablation in order to maximize radioiodine uptake [9-13]. However, the literature does not specify the duration of treatment suspension when it relates to individuals with cardiac comorbidities such as advanced heart failure. Five days without methimazole lead to a QTc of 607 ms, which resulted in VF in our patient. Thus, in patients with preexisting heart failure, discontinuation of antithyroid medication should be followed up with careful QTc monitoring prior to radioiodine ablation therapy.
Case presentation
The patient is a 62-year-old female with heart failure with reduced ejection fraction (HFrEF) from nonischemic cardiomyopathy (ejection fraction of 25%), automatic implantable cardioverter-defibrillator (AICD), hypertension, and Graves’ disease who presented after an episode of syncope at home. The patient stated that she was standing by her dresser when she suddenly started having palpitations, diaphoresis, and nausea. After that, she lost consciousness for a few seconds and fell to the floor (no head trauma). She denied any prodromal dizziness, light-headedness, or vertigo. The patient was diagnosed with Graves’ disease nine months prior to presentation. The patient stated that she was instructed by her endocrinologist to discontinue her methimazole for one week as she was scheduled to undergo elective radioiodine ablation of the thyroid. A recent thyroid uptake study showed 83% homogeneous uptake in the thyroid, consistent with graves thyrotoxicosis. The patient presented to the hospital five days after discontinuing her methimazole. She also reported palpitations, poor appetite, feeling anxious, and fatigue since stopping her medication. Home medications included aspirin 81 mg daily, metoprolol succinate ER 25 mg daily, sacubitril/valsartan 24/26 mg twice daily, spironolactone 25 mg daily, furosemide 40 mg daily, and methimazole 20 mg daily. The patient denied any past surgical history except for AICD placement. Social and family histories were significant only for Graves' disease in biological mother.
On admission, patient vitals were a pulse of 90 (regular), blood pressure of 104/58, respiratory rate of 18, and oxygen saturation of 100% on room air. Physical examination was unremarkable. Patients labs were significant for TSH of less than 0.005 (reference range 0.270-4.200 mcIU/mL), free T3 of 21.3 (reference range 0.20-4.40 pg/mL), and free T4 of greater than 7.77 (reference range 0.90-1.71 ng/dL). chest X-ray was negative for acute pathology. Initial ECG showed nonspecific intraventricular conduction delay and severe QTc prolongation of 607 ms (Figure 1). Medical record review showed patient recently followed up with a primary care physician who obtained thyroid studies and ECG. The patient’s QTc interval three weeks prior to admission was 437 (Figure 2). Thyroid function testing showed TSH of less than 0.005, free T4 of 4.7, and free T3 of 8.80. During her visit, methimazole was increased from 10 mg daily to 20 mg daily. Thus, the patient’s QTc increased from 437 ms to 607 ms (Figures 1 and 2) after discontinuing methimazole for five days. AICD interrogation revealed the patient had an episode of VF (same time as syncope occurred) and received an appropriate shock (Figure 3). AICD also showed frequent premature ventricular contractions (PVCs) prior to VF (Figure 4). Although not apparent on our patient’s AICD interrogation, the PVCs could have fallen on a T-wave from a previous contraction enabling the “R-on-T” phenomenon, which possibly triggered her VF [14]. The patient was found to have frequent PVCs on both AICD and in-hospital ECGs (Figures 1 and 4). Patient’s magnesium on admission was 2.1 (reference range 1.7-2.6 mg/dL) and potassium was 3.9 (reference range 3.5-5.1 mmol/L). Troponin and Pro-BNP were within normal limits. Transthoracic echocardiogram (TTE) showed a stable ejection fraction of 25%, no acute wall motion abnormalities, and no new structural pathologies when compared to the previous TTE done six months ago. Therefore, the likelihood of an electrolyte abnormality, myocardial ischemia or infarct, or new structural abnormality as the cause of VF was less likely. Further record review traced the patient’s diagnosis of hyperthyroidism to nine months ago, where she had a QTc of 397 (Figure 2). Thyroid studies showed TSH <0.005, free T4 of 2.08, and normal free T3 at 4.05.
Figure 1 QTc Improvement With Methimazole Treatment
Image shows improving QTc interval after treatment with high-dose methimazole (30 mg every 6 hours). After >24 hours of treatment, QTc interval improved from 607 to 431 and after >48 hours of treatment QTc improved to 399. QTc: corrected QT interval for heart rate.
Figure 2 Relationship Between QTc and Free T4
Image shows a positive correlation between QTc interval and the patient’s free thyroxine (T4). In March 2019, free T4 was 2.08 and QTc was 297 ms. In November 2019, free T4 increased to 4.70 and QTc increased to 437 ms.
Figure 3 Ventricular Fibrillation on AICD Interrogation
AICD interrogation revealed VF, which can be seen on the ventricular electrogram (V) on the AICD (black box). The onset of the VF is labeled with the blue arrow and the red arrow signifies the 40-Joule defibrillation shock, which converted the patient to sinus rhythm. VF: ventricular fibrillation; FF: far-field electrogram; AV: marker channel; V: ventricular electrogram; A: atrial electrogram; AICD: automatic implantable cardioverter-defibrillators.
Figure 4 PVCs Prior to Ventricular Fibrillation: R-on-T Phenomena
AICD detected PVCs prior to VF. PVCs (red arrows) can be seen on the ventricular electrogram (V). These PVCs supports the assumption that along with QTc prolongation, the PVCs could have resulted in the “R on T” phenomena, which triggered the VF. FF: far-field electrogram; AV: marker channel; V: ventricular electrogram; A: atrial electrogram; PVC: premature ventricular contraction.
Endocrinology was consulted and recommended the initiation of methimazole at a dose of 30 mg every six hours. EP Cardiology also recommended the initiation of antithyroid medication, avoidance of QT-prolonging drugs, maintenance of potassium above 4 and magnesium above 2, and serial ECG for QTc monitor. On day 2 of admission, and after receiving a high dose of methimazole for 24 hours (onset of action 12-16 hours), repeat ECG showed QTc of 431 (Figure 1). On day 3 of admission, QTc was 399 (Figure 1). The patient was discharged home on 30 mg methimazole twice daily with instructions to follow up with her endocrinologist and cardiologist within one week. A follow-up with the patient revealed that radioiodine ablation was postponed until the patient became euthyroid; discussion regarding potential lifelong antithyroid medication instead of ablation was being considered. Post-discharge AICD interrogation did not reveal any further ventricular arrhythmias.
Discussion
Thyroid hormone whether in its absence or excess seems to be able to cause QTc prolongation. The mechanism by which both hypothyroidism and hyperthyroidism can cause ventricular repolarization delay/OTc prolongation is not well understood. Literature review shows that in the case of hypothyroidism, there could be a combination of disturbances leading to QTc prolongation. Studies show that in hypothyroidism, there is an alteration of autonomic modulation of the heart leading to sympathovagal imbalance and an increased inhomogeneity of ventricular recovery times [8,15,16]. Furthermore, in a study conducted on guinea pigs, there was a decrease in the slow component of delayed rectifier K current (IKs), believed to be a major factor in disrupting ventricular repolarization [16,17].
Numerous studies have shown a strong association between hyperthyroidism and QTc prolongation. A positive correlation between free T4 and the degree of QT prolongation was seen; patients with higher levels of free T4 had longer QTc duration [1,3-8]. This positive correlation was present with our patient: as free T4 increased, QTc also increased (Table 1). Normalization of free T4 leads and achievement of the euthyroid state has been shown to normalize QTc duration in hyperthyroid patients [4]. Although repeat-free T4 was not done in our patient after high dose methimazole treatment, serial QTc did show significant and continued improvement (Figure 1 and Table 1). The pathophysiology of QTc prolongation due to a hyperthyroid state is not well understood. A few studies and proposed theories have explained the possible mechanism by which thyroid hormone increases ventricle repolarization and thus QTc. One theory focuses on the effect of thyroid hormone on the cardiac myocyte Na/K1 ATPase receptor. It is proposed that increased activity in this receptor secondary to the action of T4 leads to increased intracellular potassium, resulting in membrane hyperpolarization and higher QTc interval [4,5,8]. A separate study done on rats showed increased gene expression of the Na/K1 ATPase receptor after transplanted hearts were treated with T4 [4]. These findings suggest that there is a possible dose-dependent effect of T4 on the intracellular potassium of cardiac myocytes and, in turn, ventricle repolarization manifests as prolonged QTc [4]. Although very rare, new-onset thyrotoxicosis can precipitate VF theoretically by inducing coronary vasospasm leading to myocardial ischemia [1]. However, no evidence of ischemia was noted in our patient as she did not complain of angina; cardiac enzymes were within normal limits throughout admission; ECG did not show evidence of ischemia; TTE was negative for acute wall motion abnormality.
Patients with HFrEF and Graves' disease are at higher risk for cardiac arrhythmias than patients without heart failure. Maladaptive hypertrophic and fibrotic myocardial remodeling in advanced heart failure can predispose a patient to a spectrum of ventricular arrhythmias [1]. Discontinuation of medications such as methimazole in a patient with advanced heart failure can further increase the risk for ventricular arrhythmias. Our patient was instructed to discontinue medications in order to decrease the risk of radioiodine ablation failure. A meta-analysis of 14 randomized controlled trials with a total of 1306 participants showed that the continuation of antithyroid drugs in the week prior to radioiodine ablation increased the rate of ablation failure [13]. The efficacy of radioiodine therapy was reduced when the antithyroid medication was continued during ablation. Research shows that not only did radioiodine have a lower uptake and shorter half-life, but also there was a varied distribution of the radioiodine throughout the thyroid [12].
The minimum duration for withdrawal of treatment, prior to radioiodine ablation, has not been clearly established. The World Journal of Nuclear Medicine and the Society of Nuclear Medicine recommend three-day withdrawal as it has been shown to be effective in treating Graves’ disease without exacerbating hyperthyroidism. Yet, controlled clinical trials and comparative studies show that a two-day withdrawal is sufficient to restore the efficacy of radioiodine for thyroid ablation [9-12]. In the comparative study, patients in a two-day antithyroid withdrawal regimen were examined prospectively using radioiodine uptake, serum-free T4, and an outcome of therapy. These parameters were compared to those in a seven-day withdrawal regimen retrospectively. The results showed no statistically significant difference in radioiodine uptake in the two-day withdrawal group compared to the seven-day withdrawal group. The mean serum-free T4 measured 24 hours after radioiodine therapy revealed that the seven-day group had significantly higher levels than the two-day group. Thus, this study shows that the two-day withdrawal period had similar results for uptake and did not exacerbate hyperthyroidism when compared to the seven-day withdrawal period [10]. In the controlled clinical trial, radioiodine kinetics was studied under continued thiamazole medication and after discontinuation for one to two days in 316 patients. The results showed that when the antithyroid medication was discontinued for at least two days, radioiodine uptake was near normal; however, uptake within one day of discontinuation was reduced. Patients in the continued thiamazole medication group showed a decreased uptake by a factor of 2.5 [12].
A two-day withdrawal period may be useful for high-risk patients with cardiac comorbidities such as advanced heart failure. In our patient, discontinuation of methimazole for two days instead of seven days could have prevented thyrotoxicosis and in turn VF from QTc prolongation. It is evident from our patient's ECGs that serum T4 levels had a positive correlation with QTc interval (Table 1). Severely elevated T4 can lead to dangerously prolonged QTc resulting in ventricular arrhythmias such as VF or TdP. The risk of prolongation of QTc is likely further increased in our patient given her advanced heart failure. Withdrawal of treatment should be minimized and if indicated to the least number of days. QTc should be monitored frequently when the withdrawal is indicated, especially regarding patients with cardiac comorbidities. Further research and concrete guidelines for the duration of withdrawal of antithyroid medication prior to radioiodine ablation in high-risk patients is needed.
Table 1 Positive Correlation Between Correct QT Interval and Free Thyroxine
The table shows a positive correlation between QTc and free T4 levels in our patient. As free T4 levels increased the QTc of our patient also increased. The QTc interval dramatically decreased from 607 ms to 431 ms after receiving >24 hours of high dose methimazole (30 mg every six hours). Free T4 was not checked after initial testing during the December 2020 admission. Corrected QT interval (QTc) is in milliseconds; free thyroxine level (T4) is in nanograms per deciliter.
March 2019 November 2019 December 2020: Day 1 December 2020: Day 2 December 2020: Day 3
Corrected QT interval 397 437 607 431 399
Free thyroxine level 2.08 4.7 >7.77 Not checked Not checked
Conclusions
In this case, the patient’s syncopal episode due to VF may have been due to severe QT prolongation in the setting of thyrotoxicosis from medication withdrawal. Given her history of nonischemic cardiomyopathy with an ejection fraction of 25%, the risk for ventricular arrhythmias is already elevated. Caution should be taken when withdrawing antithyroid medication in patients with advanced heart failure as the risks for severe QTc prolongation and subsequent malignant ventricular arrhythmias may be increased. If a withdrawal is indicated, the least amount of duration should be chosen and frequent monitoring of QTc should be performed.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | 24/26 MG TWICE DAILY | DrugDosageText | CC BY | 33692927 | 19,062,069 | 2021-02-06 |
What was the outcome of reaction 'Ventricular fibrillation'? | Ventricular Fibrillation: Potential Deadly Consequence of Discontinuation of Methimazole Prior to Radioiodine Ablation.
The following case involves a 62-year-old female patient suffering from heart failure with reduced ejection fraction (HFrEF) secondary to non-ischemic cardiomyopathy and Graves disease, who developed ventricular fibrillation (VF) after discontinuation of methimazole in preparation for radioiodine ablation. Electrocardiogram (ECG) showed a severely prolonged QTc in the setting of thyrotoxicosis, which significantly improved with high dose methimazole. VF secondary to thyrotoxicosis has rarely been reported and the literature review shows scarce data on its mechanism. Our case demonstrates not only a possible mechanism for the arrhythmia, but also highlights a potential risk factor for it. The report details how discontinuing antithyroid medication leads to VF in our patient and reviews the current literature on antithyroid withdrawal prior to radioiodine ablation therapy. Caution should be taken when discontinuing antithyroid medications in patients with advanced heart failure as potentially lethal ventricular arrhythmias can ensue.
Introduction
Hyperthyroidism imposes various cardiovascular complications and hemodynamic changes like increased contractility, increased preload, and decreased systemic vascular resistance, which all result in increased cardiac output [1,2]. The most common cardiac complication is atrial fibrillation which occurs in approximately 15% of overtly hyperthyroid patients [3]. The occurrence of dangerous arrhythmias such as ventricular fibrillation (VF), although rare, can cause sudden cardiac death [4]. Malignant ventricular arrhythmias secondary to QT prolongation from thyrotoxicosis are seldom encountered in the inpatient setting. Factors that contribute to a fatal arrhythmia are thyrotoxicosis in the setting of an already weakened heart, seen in our patient. Literature review shows that ventricle repolarization is greatly affected in hyperthyroidism [3-5]. Ventricular repolarization is assessed using the QT interval corrected for the heart rate (QTc) on an electrocardiogram (ECG). Research shows a significant positive correlation between QTc and thyroid hormones, especially free T4 levels. However, the mechanism and pathophysiology are not well understood [4-8]. The correlation has even been reported in patients with subclinical hyperthyroidism [7]. Prolonged QTc is associated with an increased risk for lethal arrhythmias such as torsade de Pointes (TdP) or VF. Thyrotoxicosis from antithyroid withdrawal for radioiodine ablation has been reported, however, serious adverse events such as VF have rarely been reported. This case shows after five days of discontinuing methimazole, the QTc increased to dangerous levels, triggering VF in our patient. Various withdrawal periods have been reported: current guidelines dictate that antithyroid medications should be held for three to seven days prior to radioiodine ablation in order to maximize radioiodine uptake [9-13]. However, the literature does not specify the duration of treatment suspension when it relates to individuals with cardiac comorbidities such as advanced heart failure. Five days without methimazole lead to a QTc of 607 ms, which resulted in VF in our patient. Thus, in patients with preexisting heart failure, discontinuation of antithyroid medication should be followed up with careful QTc monitoring prior to radioiodine ablation therapy.
Case presentation
The patient is a 62-year-old female with heart failure with reduced ejection fraction (HFrEF) from nonischemic cardiomyopathy (ejection fraction of 25%), automatic implantable cardioverter-defibrillator (AICD), hypertension, and Graves’ disease who presented after an episode of syncope at home. The patient stated that she was standing by her dresser when she suddenly started having palpitations, diaphoresis, and nausea. After that, she lost consciousness for a few seconds and fell to the floor (no head trauma). She denied any prodromal dizziness, light-headedness, or vertigo. The patient was diagnosed with Graves’ disease nine months prior to presentation. The patient stated that she was instructed by her endocrinologist to discontinue her methimazole for one week as she was scheduled to undergo elective radioiodine ablation of the thyroid. A recent thyroid uptake study showed 83% homogeneous uptake in the thyroid, consistent with graves thyrotoxicosis. The patient presented to the hospital five days after discontinuing her methimazole. She also reported palpitations, poor appetite, feeling anxious, and fatigue since stopping her medication. Home medications included aspirin 81 mg daily, metoprolol succinate ER 25 mg daily, sacubitril/valsartan 24/26 mg twice daily, spironolactone 25 mg daily, furosemide 40 mg daily, and methimazole 20 mg daily. The patient denied any past surgical history except for AICD placement. Social and family histories were significant only for Graves' disease in biological mother.
On admission, patient vitals were a pulse of 90 (regular), blood pressure of 104/58, respiratory rate of 18, and oxygen saturation of 100% on room air. Physical examination was unremarkable. Patients labs were significant for TSH of less than 0.005 (reference range 0.270-4.200 mcIU/mL), free T3 of 21.3 (reference range 0.20-4.40 pg/mL), and free T4 of greater than 7.77 (reference range 0.90-1.71 ng/dL). chest X-ray was negative for acute pathology. Initial ECG showed nonspecific intraventricular conduction delay and severe QTc prolongation of 607 ms (Figure 1). Medical record review showed patient recently followed up with a primary care physician who obtained thyroid studies and ECG. The patient’s QTc interval three weeks prior to admission was 437 (Figure 2). Thyroid function testing showed TSH of less than 0.005, free T4 of 4.7, and free T3 of 8.80. During her visit, methimazole was increased from 10 mg daily to 20 mg daily. Thus, the patient’s QTc increased from 437 ms to 607 ms (Figures 1 and 2) after discontinuing methimazole for five days. AICD interrogation revealed the patient had an episode of VF (same time as syncope occurred) and received an appropriate shock (Figure 3). AICD also showed frequent premature ventricular contractions (PVCs) prior to VF (Figure 4). Although not apparent on our patient’s AICD interrogation, the PVCs could have fallen on a T-wave from a previous contraction enabling the “R-on-T” phenomenon, which possibly triggered her VF [14]. The patient was found to have frequent PVCs on both AICD and in-hospital ECGs (Figures 1 and 4). Patient’s magnesium on admission was 2.1 (reference range 1.7-2.6 mg/dL) and potassium was 3.9 (reference range 3.5-5.1 mmol/L). Troponin and Pro-BNP were within normal limits. Transthoracic echocardiogram (TTE) showed a stable ejection fraction of 25%, no acute wall motion abnormalities, and no new structural pathologies when compared to the previous TTE done six months ago. Therefore, the likelihood of an electrolyte abnormality, myocardial ischemia or infarct, or new structural abnormality as the cause of VF was less likely. Further record review traced the patient’s diagnosis of hyperthyroidism to nine months ago, where she had a QTc of 397 (Figure 2). Thyroid studies showed TSH <0.005, free T4 of 2.08, and normal free T3 at 4.05.
Figure 1 QTc Improvement With Methimazole Treatment
Image shows improving QTc interval after treatment with high-dose methimazole (30 mg every 6 hours). After >24 hours of treatment, QTc interval improved from 607 to 431 and after >48 hours of treatment QTc improved to 399. QTc: corrected QT interval for heart rate.
Figure 2 Relationship Between QTc and Free T4
Image shows a positive correlation between QTc interval and the patient’s free thyroxine (T4). In March 2019, free T4 was 2.08 and QTc was 297 ms. In November 2019, free T4 increased to 4.70 and QTc increased to 437 ms.
Figure 3 Ventricular Fibrillation on AICD Interrogation
AICD interrogation revealed VF, which can be seen on the ventricular electrogram (V) on the AICD (black box). The onset of the VF is labeled with the blue arrow and the red arrow signifies the 40-Joule defibrillation shock, which converted the patient to sinus rhythm. VF: ventricular fibrillation; FF: far-field electrogram; AV: marker channel; V: ventricular electrogram; A: atrial electrogram; AICD: automatic implantable cardioverter-defibrillators.
Figure 4 PVCs Prior to Ventricular Fibrillation: R-on-T Phenomena
AICD detected PVCs prior to VF. PVCs (red arrows) can be seen on the ventricular electrogram (V). These PVCs supports the assumption that along with QTc prolongation, the PVCs could have resulted in the “R on T” phenomena, which triggered the VF. FF: far-field electrogram; AV: marker channel; V: ventricular electrogram; A: atrial electrogram; PVC: premature ventricular contraction.
Endocrinology was consulted and recommended the initiation of methimazole at a dose of 30 mg every six hours. EP Cardiology also recommended the initiation of antithyroid medication, avoidance of QT-prolonging drugs, maintenance of potassium above 4 and magnesium above 2, and serial ECG for QTc monitor. On day 2 of admission, and after receiving a high dose of methimazole for 24 hours (onset of action 12-16 hours), repeat ECG showed QTc of 431 (Figure 1). On day 3 of admission, QTc was 399 (Figure 1). The patient was discharged home on 30 mg methimazole twice daily with instructions to follow up with her endocrinologist and cardiologist within one week. A follow-up with the patient revealed that radioiodine ablation was postponed until the patient became euthyroid; discussion regarding potential lifelong antithyroid medication instead of ablation was being considered. Post-discharge AICD interrogation did not reveal any further ventricular arrhythmias.
Discussion
Thyroid hormone whether in its absence or excess seems to be able to cause QTc prolongation. The mechanism by which both hypothyroidism and hyperthyroidism can cause ventricular repolarization delay/OTc prolongation is not well understood. Literature review shows that in the case of hypothyroidism, there could be a combination of disturbances leading to QTc prolongation. Studies show that in hypothyroidism, there is an alteration of autonomic modulation of the heart leading to sympathovagal imbalance and an increased inhomogeneity of ventricular recovery times [8,15,16]. Furthermore, in a study conducted on guinea pigs, there was a decrease in the slow component of delayed rectifier K current (IKs), believed to be a major factor in disrupting ventricular repolarization [16,17].
Numerous studies have shown a strong association between hyperthyroidism and QTc prolongation. A positive correlation between free T4 and the degree of QT prolongation was seen; patients with higher levels of free T4 had longer QTc duration [1,3-8]. This positive correlation was present with our patient: as free T4 increased, QTc also increased (Table 1). Normalization of free T4 leads and achievement of the euthyroid state has been shown to normalize QTc duration in hyperthyroid patients [4]. Although repeat-free T4 was not done in our patient after high dose methimazole treatment, serial QTc did show significant and continued improvement (Figure 1 and Table 1). The pathophysiology of QTc prolongation due to a hyperthyroid state is not well understood. A few studies and proposed theories have explained the possible mechanism by which thyroid hormone increases ventricle repolarization and thus QTc. One theory focuses on the effect of thyroid hormone on the cardiac myocyte Na/K1 ATPase receptor. It is proposed that increased activity in this receptor secondary to the action of T4 leads to increased intracellular potassium, resulting in membrane hyperpolarization and higher QTc interval [4,5,8]. A separate study done on rats showed increased gene expression of the Na/K1 ATPase receptor after transplanted hearts were treated with T4 [4]. These findings suggest that there is a possible dose-dependent effect of T4 on the intracellular potassium of cardiac myocytes and, in turn, ventricle repolarization manifests as prolonged QTc [4]. Although very rare, new-onset thyrotoxicosis can precipitate VF theoretically by inducing coronary vasospasm leading to myocardial ischemia [1]. However, no evidence of ischemia was noted in our patient as she did not complain of angina; cardiac enzymes were within normal limits throughout admission; ECG did not show evidence of ischemia; TTE was negative for acute wall motion abnormality.
Patients with HFrEF and Graves' disease are at higher risk for cardiac arrhythmias than patients without heart failure. Maladaptive hypertrophic and fibrotic myocardial remodeling in advanced heart failure can predispose a patient to a spectrum of ventricular arrhythmias [1]. Discontinuation of medications such as methimazole in a patient with advanced heart failure can further increase the risk for ventricular arrhythmias. Our patient was instructed to discontinue medications in order to decrease the risk of radioiodine ablation failure. A meta-analysis of 14 randomized controlled trials with a total of 1306 participants showed that the continuation of antithyroid drugs in the week prior to radioiodine ablation increased the rate of ablation failure [13]. The efficacy of radioiodine therapy was reduced when the antithyroid medication was continued during ablation. Research shows that not only did radioiodine have a lower uptake and shorter half-life, but also there was a varied distribution of the radioiodine throughout the thyroid [12].
The minimum duration for withdrawal of treatment, prior to radioiodine ablation, has not been clearly established. The World Journal of Nuclear Medicine and the Society of Nuclear Medicine recommend three-day withdrawal as it has been shown to be effective in treating Graves’ disease without exacerbating hyperthyroidism. Yet, controlled clinical trials and comparative studies show that a two-day withdrawal is sufficient to restore the efficacy of radioiodine for thyroid ablation [9-12]. In the comparative study, patients in a two-day antithyroid withdrawal regimen were examined prospectively using radioiodine uptake, serum-free T4, and an outcome of therapy. These parameters were compared to those in a seven-day withdrawal regimen retrospectively. The results showed no statistically significant difference in radioiodine uptake in the two-day withdrawal group compared to the seven-day withdrawal group. The mean serum-free T4 measured 24 hours after radioiodine therapy revealed that the seven-day group had significantly higher levels than the two-day group. Thus, this study shows that the two-day withdrawal period had similar results for uptake and did not exacerbate hyperthyroidism when compared to the seven-day withdrawal period [10]. In the controlled clinical trial, radioiodine kinetics was studied under continued thiamazole medication and after discontinuation for one to two days in 316 patients. The results showed that when the antithyroid medication was discontinued for at least two days, radioiodine uptake was near normal; however, uptake within one day of discontinuation was reduced. Patients in the continued thiamazole medication group showed a decreased uptake by a factor of 2.5 [12].
A two-day withdrawal period may be useful for high-risk patients with cardiac comorbidities such as advanced heart failure. In our patient, discontinuation of methimazole for two days instead of seven days could have prevented thyrotoxicosis and in turn VF from QTc prolongation. It is evident from our patient's ECGs that serum T4 levels had a positive correlation with QTc interval (Table 1). Severely elevated T4 can lead to dangerously prolonged QTc resulting in ventricular arrhythmias such as VF or TdP. The risk of prolongation of QTc is likely further increased in our patient given her advanced heart failure. Withdrawal of treatment should be minimized and if indicated to the least number of days. QTc should be monitored frequently when the withdrawal is indicated, especially regarding patients with cardiac comorbidities. Further research and concrete guidelines for the duration of withdrawal of antithyroid medication prior to radioiodine ablation in high-risk patients is needed.
Table 1 Positive Correlation Between Correct QT Interval and Free Thyroxine
The table shows a positive correlation between QTc and free T4 levels in our patient. As free T4 levels increased the QTc of our patient also increased. The QTc interval dramatically decreased from 607 ms to 431 ms after receiving >24 hours of high dose methimazole (30 mg every six hours). Free T4 was not checked after initial testing during the December 2020 admission. Corrected QT interval (QTc) is in milliseconds; free thyroxine level (T4) is in nanograms per deciliter.
March 2019 November 2019 December 2020: Day 1 December 2020: Day 2 December 2020: Day 3
Corrected QT interval 397 437 607 431 399
Free thyroxine level 2.08 4.7 >7.77 Not checked Not checked
Conclusions
In this case, the patient’s syncopal episode due to VF may have been due to severe QT prolongation in the setting of thyrotoxicosis from medication withdrawal. Given her history of nonischemic cardiomyopathy with an ejection fraction of 25%, the risk for ventricular arrhythmias is already elevated. Caution should be taken when withdrawing antithyroid medication in patients with advanced heart failure as the risks for severe QTc prolongation and subsequent malignant ventricular arrhythmias may be increased. If a withdrawal is indicated, the least amount of duration should be chosen and frequent monitoring of QTc should be performed.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33692927 | 19,062,069 | 2021-02-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal exposure during pregnancy'. | Managing asymptomatic severe rheumatic mitral stenosis in pregnancy: a case report.
Rheumatic heart disease (RHD) is a disease of disparity most prevalent in developing countries and among immigrant populations. Mitral stenosis (MS) is a common sequalae of RHD and affects females disproportionately more than males. Rheumatic MS remains a significant management challenge as severe MS is usually poorly tolerated in pregnancy due to haemodynamic changes and increased cardiovascular demands of progressing pregnancy. Pregnancy remains contraindicated in current management guidelines based on expert consensus, due to a paucity of evidence-based literature.
A 28-year-old aboriginal woman with known severe MS was found to be pregnant during routine health review, despite contraceptive efforts. Echocardiography demonstrated mean mitral valve (MV) gradient 14 mmHg; stress echocardiography demonstrated increased MV gradient 28-32 mmHg at peak exercise and post-exercise pulmonary artery pressure 56 + 3 mmHg with marked dynamic D-shaped septal flattening. Left ventricular systolic function remained preserved. She remained remarkably asymptomatic and underwent successful elective induction of labour at 34 weeks. Postpartum, she remained euvolaemic despite worsening MV gradients and new atrial fibrillation (AF). She subsequently underwent balloon mitral valvuloplasty with good result.
Severe rheumatic MS in pregnancy carries significant morbidity and mortality, due to an already fragile predisposition towards heart failure development compounded by altered haemodynamics. Pregnancy avoidance and valvular intervention prior to conception or in the second trimester remain the mainstay of MS management; however, we present an encouraging case of successful near-term pregnancy with minimal complications in a medically managed asymptomatic patient with critical MS, who subsequently underwent valvular intervention post-partum.
Learning points
There is limited information regarding the management of severe mitral stenosis (MS) in women of childbearing age or who are pregnant, particularly if they remain asymptomatic.
Serial echocardiography combined with stress testing and physiological assessment for surveillance of mitral valve gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, and timing of percutaneous balloon mitral valvuloplasty (BMV).
Percutaneous BMV may be safely deferred until postpartum in women with severe MS who remain asymptomatic, to minimize procedural risks for mother and developing foetus.
Introduction
Left-sided stenotic valvulopathies, including mitral stenosis (MS), remain a feared entity in pregnancy due to the effects of altered physiology including increased intravascular volume, cardiac output and heart rate, and decreased systemic vascular resistance and systolic blood pressure1 which increases MS complication risks. Maternal complications include pulmonary oedema, arrhythmias, and increased mortality, whilst foetal complications include preterm delivery, intrauterine growth restriction, and foetal death.1
The risk of developing heart failure corresponds with MS severity.2 Severe MS is usually poorly tolerated in pregnancy, with 67% of women developing peripartum heart failure even if previously asymptomatic.2–4 This is contributed to by increased heart rates antepartum, resulting in shortened diastolic filling time, increased left atrial pressure, and pulmonary venous pressures predisposing to heart failure.4 Pregnancy is contraindicated in current guidelines, which recommend percutaneous valvular intervention in women with moderate or severe MS contemplating pregnancy5 (Figure 1).
Figure 1 Managing severe rheumatic mitral stenosis in pregnancy.
We present our management of a remarkably asymptomatic patient with critical MS, who presented 13 weeks antepartum despite contraceptive efforts and without preconception valve intervention. The valvular intervention occurred postpartum, with good outcomes for both mother and child.
Timeline
Case presentation
A 28-year-old aboriginal Australian woman from a remote community with known severe MS was found to be 13 weeks pregnant despite contraceptive depot injections, after presenting for routine review at the local community clinic.
She had a previous episode of acute rheumatic fever aged 10. She had been adherent with standard secondary prophylaxis regimen since but subsequently developed severe mitral stenosis necessitating balloon mitral valvuloplasty (BMV) aged 14. Prior to pregnancy, her last echocardiogram in 2018 demonstrated severe rheumatic MS with mean pressure gradient (mPG) 17 mmHg, mitral valve area (MVA) 0.9 cm2, and mild pulmonary hypertension with estimated pulmonary artery pressure (EPAP) 30 mmHg + right atrial pressure (RAP) 3 mmHg. Left ventricular systolic function was preserved. She remained clinically asymptomatic and was therefore managed conservatively. Additionally, she received pregnancy-avoidance counselling and agreed to commence 3-monthly contraceptive depot injections. She did not have other medical conditions or regular medications.
Due to the cultural significance of pregnancy within her community, she elected to continue her pregnancy fully cognisant of the increased risks of adverse outcomes secondary to her valvulopathy. She was subsequently referred for Cardiology Specialist input.
She remained remarkably asymptomatic despite critical MS. Physical examination demonstrated dual heart sounds with an additional soft diastolic murmur. There was no evidence of pulmonary congestion of peripheral oedema. Her NTproBNP level was 136 ng/L. She had mild normocytic anaemia (Hb 106 g/L; mean cell volume 85.8 fL); electrolytes and creatinine levels were normal (sodium 135 mmol/L, potassium 3.8 mmol/L, creatinine 54 µmol/L, estimated glomerular filtrate rate >90 mL/min/1.73 m2). Transthoracic echocardiography (TTE) at 13 weeks antepartum demonstrated a doming hockey stick appearance of the anterior mitral valve leaflet, thickened immobile posterior mitral leaflet with markedly restricted excursion resulting in severe mitral stenosis (mPG 14 mmHg), mitral valve area 0.4 cm2, severely dilated left atrium (indexed volume 50 mL/m2), mild pulmonary hypertension (EPAP 34 + 3 mmHg). Stress echocardiogram performed at 20 weeks antepartum demonstrated mitral valve (MV) mPG 28–32 mmHg at peak exercise, and post-exercise EPAP 56 + 3 mmHg with development of D-shaped septal flattening (Figure 2). She did not desaturate during this test. Given her minimal symptoms, she was successfully managed in a culturally sensitive manner in her remote community until the early third trimester, where she was electively admitted to a local tertiary hospital before transfer to a tertiary centre with cardiothoracic services for valve intervention prior to delivery.
Figure 2 Exercise stress echocardiogram demonstrating (A) left ventricular at rest and (B) marked septal D-shape flattening with peak exercise.
Serial TTEs during antepartum demonstrated critical but stable MV gradients (mPG 19–21 mmHg; Figure 3). She was also commenced on beta-blocker therapy to minimize maternal tachycardia. She remained clinically and haemodynamically stable until the planned induction of labour at 34 weeks. This was subsequently converted to caesarean section due to abnormal foetal cardiotocography, with the delivery of a healthy male baby.
Figure 3 Transthoracic echocardiogram demonstrating (A) severe mitral stenosis and (B) pulmonary hypertension.
Beta-blocker therapy was held for 24 h post-partum. The reason for this was unclear however was re-initiated together with digoxin due to worsening MV gradients (mPG 29 mmHg), EPAP 57 ± 3 mmHg (Figure 4), and development of palpitations secondary to new atrial fibrillation (AF) Day 2 postpartum. She remained clinically euvolaemic, and following consultation with her treating teams, she underwent elective BMV Day 8 postpartum with improved MV gradients and MVA (Figure 5). She remained well and was discharged Day 10 post-partum post-contraceptive implantation. She remained well on telephone review Day 2 post-discharge, prior to return to her local community.
Figure 4 First postpartum transthoracic echocardiogram demonstrating (A) critical mitral stenosis and (B) pulmonary hypertension.
Figure 5 Balloon inflation during balloon mitral valvuloplasty. (A) Distal balloon inflation. (B) Inflation of proximal and middle balloon, with waist in mid-portion of balloon demonstrating mitral stenosis. (C) Full balloon inflation. Post-balloon mitral valvuloplasty transthoracic echocardiogram demonstrating (D) moderate mitral stenosis and (E) mild pulmonary hypertension.
Discussion
Whilst not common in developed countries, MS accounts for 9.5% of all valvular heart disease in Europe. Rheumatic heart disease (RHD) remains the most common aetiology.6 In Australia, RHD is a striking disease of disparity, where 89% of affected Australians identify as Aboriginal or Torres Strait Islander, representing a rate 6.6 times higher than non-Indigenous Australians.7 47% of Aboriginal or Torres Strait Islanders affected are aged under 20 years.7 Women account for 61% of the total indigenous RHD burden,7 attracting the greatest risk of poor outcomes, especially during pregnancy.
Pregnancy remains a World Health Organisation (WHO) Class IV contraindication in severe MS, due to maternal and foetal morbidity and mortality;5 however, there is a paucity of information regarding the management of severe MS in women of childbearing age or who are pregnant, particularly if they remain asymptomatic. The current guidelines are based on expert consensus which strongly recommends pregnancy avoidance or consideration of pregnancy termination, and do not address or acknowledge cultural sensitivities, varying levels of medical literacy or socioeconomic constraints of patient populations where RHD is likely more prevalent. Management of an already pregnant patient focuses on a combination of pharmacological agents including beta-blockers and diuretics, and clinical monitoring to identify the development of intervention indications.5,8 Percutaneous valvular intervention is recommended preconception. The intrapartum intervention has been reported but only in persistently symptomatic patients between second and third trimesters9 to consider organogenesis of the foetus. This does not take into account the hyperactive mammary tissue exposed to radiation, or the longer-term risk of childhood malignancy. Current guidelines do not account for many of these issues, or the timing and utility of serial echocardiographic assessments to guide percutaneous intervention as pregnancy develops.
This case demonstrates a number of important points. Achievement of pregnancy avoidance may not always be achieved despite its prescription. Serial echocardiography in combination with stress testing and physiological assessment for the surveillance of MV gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, as well as the timing of percutaneous BMV. We have also demonstrated the safe and successful deferral of percutaneous BMV until post-partum in asymptomatic patients, protecting both the developing foetus and also maternal mammary tissue which remains increasingly active postpartum from potentially harmful radiation.
Our case highlights the importance of patient-specific care and that further understanding of severe MS management in women of childbearing age and intrapartum is required to improve maternal and foetal outcomes.
Lead author biography
Joanne M. H. Eng-Frost is a Cardiology Advanced Trainee at Flinders Medical Centre in Adelaide, Australia. She completed a Bachelor of Science (Biomedical Science) degree with Honours in Physiology at the University of Adelaide, Australia before earning a Doctor of Medicine (MD) degree at Flinders University, Australia. Her clinical interests include structural heart disease and interventional cardiology.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab010_Supplementary_Data Click here for additional data file. | LABETALOL\LABETALOL HYDROCHLORIDE, METOPROLOL | DrugsGivenReaction | CC BY-NC | 33693306 | 20,151,132 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Premature baby'. | Managing asymptomatic severe rheumatic mitral stenosis in pregnancy: a case report.
Rheumatic heart disease (RHD) is a disease of disparity most prevalent in developing countries and among immigrant populations. Mitral stenosis (MS) is a common sequalae of RHD and affects females disproportionately more than males. Rheumatic MS remains a significant management challenge as severe MS is usually poorly tolerated in pregnancy due to haemodynamic changes and increased cardiovascular demands of progressing pregnancy. Pregnancy remains contraindicated in current management guidelines based on expert consensus, due to a paucity of evidence-based literature.
A 28-year-old aboriginal woman with known severe MS was found to be pregnant during routine health review, despite contraceptive efforts. Echocardiography demonstrated mean mitral valve (MV) gradient 14 mmHg; stress echocardiography demonstrated increased MV gradient 28-32 mmHg at peak exercise and post-exercise pulmonary artery pressure 56 + 3 mmHg with marked dynamic D-shaped septal flattening. Left ventricular systolic function remained preserved. She remained remarkably asymptomatic and underwent successful elective induction of labour at 34 weeks. Postpartum, she remained euvolaemic despite worsening MV gradients and new atrial fibrillation (AF). She subsequently underwent balloon mitral valvuloplasty with good result.
Severe rheumatic MS in pregnancy carries significant morbidity and mortality, due to an already fragile predisposition towards heart failure development compounded by altered haemodynamics. Pregnancy avoidance and valvular intervention prior to conception or in the second trimester remain the mainstay of MS management; however, we present an encouraging case of successful near-term pregnancy with minimal complications in a medically managed asymptomatic patient with critical MS, who subsequently underwent valvular intervention post-partum.
Learning points
There is limited information regarding the management of severe mitral stenosis (MS) in women of childbearing age or who are pregnant, particularly if they remain asymptomatic.
Serial echocardiography combined with stress testing and physiological assessment for surveillance of mitral valve gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, and timing of percutaneous balloon mitral valvuloplasty (BMV).
Percutaneous BMV may be safely deferred until postpartum in women with severe MS who remain asymptomatic, to minimize procedural risks for mother and developing foetus.
Introduction
Left-sided stenotic valvulopathies, including mitral stenosis (MS), remain a feared entity in pregnancy due to the effects of altered physiology including increased intravascular volume, cardiac output and heart rate, and decreased systemic vascular resistance and systolic blood pressure1 which increases MS complication risks. Maternal complications include pulmonary oedema, arrhythmias, and increased mortality, whilst foetal complications include preterm delivery, intrauterine growth restriction, and foetal death.1
The risk of developing heart failure corresponds with MS severity.2 Severe MS is usually poorly tolerated in pregnancy, with 67% of women developing peripartum heart failure even if previously asymptomatic.2–4 This is contributed to by increased heart rates antepartum, resulting in shortened diastolic filling time, increased left atrial pressure, and pulmonary venous pressures predisposing to heart failure.4 Pregnancy is contraindicated in current guidelines, which recommend percutaneous valvular intervention in women with moderate or severe MS contemplating pregnancy5 (Figure 1).
Figure 1 Managing severe rheumatic mitral stenosis in pregnancy.
We present our management of a remarkably asymptomatic patient with critical MS, who presented 13 weeks antepartum despite contraceptive efforts and without preconception valve intervention. The valvular intervention occurred postpartum, with good outcomes for both mother and child.
Timeline
Case presentation
A 28-year-old aboriginal Australian woman from a remote community with known severe MS was found to be 13 weeks pregnant despite contraceptive depot injections, after presenting for routine review at the local community clinic.
She had a previous episode of acute rheumatic fever aged 10. She had been adherent with standard secondary prophylaxis regimen since but subsequently developed severe mitral stenosis necessitating balloon mitral valvuloplasty (BMV) aged 14. Prior to pregnancy, her last echocardiogram in 2018 demonstrated severe rheumatic MS with mean pressure gradient (mPG) 17 mmHg, mitral valve area (MVA) 0.9 cm2, and mild pulmonary hypertension with estimated pulmonary artery pressure (EPAP) 30 mmHg + right atrial pressure (RAP) 3 mmHg. Left ventricular systolic function was preserved. She remained clinically asymptomatic and was therefore managed conservatively. Additionally, she received pregnancy-avoidance counselling and agreed to commence 3-monthly contraceptive depot injections. She did not have other medical conditions or regular medications.
Due to the cultural significance of pregnancy within her community, she elected to continue her pregnancy fully cognisant of the increased risks of adverse outcomes secondary to her valvulopathy. She was subsequently referred for Cardiology Specialist input.
She remained remarkably asymptomatic despite critical MS. Physical examination demonstrated dual heart sounds with an additional soft diastolic murmur. There was no evidence of pulmonary congestion of peripheral oedema. Her NTproBNP level was 136 ng/L. She had mild normocytic anaemia (Hb 106 g/L; mean cell volume 85.8 fL); electrolytes and creatinine levels were normal (sodium 135 mmol/L, potassium 3.8 mmol/L, creatinine 54 µmol/L, estimated glomerular filtrate rate >90 mL/min/1.73 m2). Transthoracic echocardiography (TTE) at 13 weeks antepartum demonstrated a doming hockey stick appearance of the anterior mitral valve leaflet, thickened immobile posterior mitral leaflet with markedly restricted excursion resulting in severe mitral stenosis (mPG 14 mmHg), mitral valve area 0.4 cm2, severely dilated left atrium (indexed volume 50 mL/m2), mild pulmonary hypertension (EPAP 34 + 3 mmHg). Stress echocardiogram performed at 20 weeks antepartum demonstrated mitral valve (MV) mPG 28–32 mmHg at peak exercise, and post-exercise EPAP 56 + 3 mmHg with development of D-shaped septal flattening (Figure 2). She did not desaturate during this test. Given her minimal symptoms, she was successfully managed in a culturally sensitive manner in her remote community until the early third trimester, where she was electively admitted to a local tertiary hospital before transfer to a tertiary centre with cardiothoracic services for valve intervention prior to delivery.
Figure 2 Exercise stress echocardiogram demonstrating (A) left ventricular at rest and (B) marked septal D-shape flattening with peak exercise.
Serial TTEs during antepartum demonstrated critical but stable MV gradients (mPG 19–21 mmHg; Figure 3). She was also commenced on beta-blocker therapy to minimize maternal tachycardia. She remained clinically and haemodynamically stable until the planned induction of labour at 34 weeks. This was subsequently converted to caesarean section due to abnormal foetal cardiotocography, with the delivery of a healthy male baby.
Figure 3 Transthoracic echocardiogram demonstrating (A) severe mitral stenosis and (B) pulmonary hypertension.
Beta-blocker therapy was held for 24 h post-partum. The reason for this was unclear however was re-initiated together with digoxin due to worsening MV gradients (mPG 29 mmHg), EPAP 57 ± 3 mmHg (Figure 4), and development of palpitations secondary to new atrial fibrillation (AF) Day 2 postpartum. She remained clinically euvolaemic, and following consultation with her treating teams, she underwent elective BMV Day 8 postpartum with improved MV gradients and MVA (Figure 5). She remained well and was discharged Day 10 post-partum post-contraceptive implantation. She remained well on telephone review Day 2 post-discharge, prior to return to her local community.
Figure 4 First postpartum transthoracic echocardiogram demonstrating (A) critical mitral stenosis and (B) pulmonary hypertension.
Figure 5 Balloon inflation during balloon mitral valvuloplasty. (A) Distal balloon inflation. (B) Inflation of proximal and middle balloon, with waist in mid-portion of balloon demonstrating mitral stenosis. (C) Full balloon inflation. Post-balloon mitral valvuloplasty transthoracic echocardiogram demonstrating (D) moderate mitral stenosis and (E) mild pulmonary hypertension.
Discussion
Whilst not common in developed countries, MS accounts for 9.5% of all valvular heart disease in Europe. Rheumatic heart disease (RHD) remains the most common aetiology.6 In Australia, RHD is a striking disease of disparity, where 89% of affected Australians identify as Aboriginal or Torres Strait Islander, representing a rate 6.6 times higher than non-Indigenous Australians.7 47% of Aboriginal or Torres Strait Islanders affected are aged under 20 years.7 Women account for 61% of the total indigenous RHD burden,7 attracting the greatest risk of poor outcomes, especially during pregnancy.
Pregnancy remains a World Health Organisation (WHO) Class IV contraindication in severe MS, due to maternal and foetal morbidity and mortality;5 however, there is a paucity of information regarding the management of severe MS in women of childbearing age or who are pregnant, particularly if they remain asymptomatic. The current guidelines are based on expert consensus which strongly recommends pregnancy avoidance or consideration of pregnancy termination, and do not address or acknowledge cultural sensitivities, varying levels of medical literacy or socioeconomic constraints of patient populations where RHD is likely more prevalent. Management of an already pregnant patient focuses on a combination of pharmacological agents including beta-blockers and diuretics, and clinical monitoring to identify the development of intervention indications.5,8 Percutaneous valvular intervention is recommended preconception. The intrapartum intervention has been reported but only in persistently symptomatic patients between second and third trimesters9 to consider organogenesis of the foetus. This does not take into account the hyperactive mammary tissue exposed to radiation, or the longer-term risk of childhood malignancy. Current guidelines do not account for many of these issues, or the timing and utility of serial echocardiographic assessments to guide percutaneous intervention as pregnancy develops.
This case demonstrates a number of important points. Achievement of pregnancy avoidance may not always be achieved despite its prescription. Serial echocardiography in combination with stress testing and physiological assessment for the surveillance of MV gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, as well as the timing of percutaneous BMV. We have also demonstrated the safe and successful deferral of percutaneous BMV until post-partum in asymptomatic patients, protecting both the developing foetus and also maternal mammary tissue which remains increasingly active postpartum from potentially harmful radiation.
Our case highlights the importance of patient-specific care and that further understanding of severe MS management in women of childbearing age and intrapartum is required to improve maternal and foetal outcomes.
Lead author biography
Joanne M. H. Eng-Frost is a Cardiology Advanced Trainee at Flinders Medical Centre in Adelaide, Australia. She completed a Bachelor of Science (Biomedical Science) degree with Honours in Physiology at the University of Adelaide, Australia before earning a Doctor of Medicine (MD) degree at Flinders University, Australia. Her clinical interests include structural heart disease and interventional cardiology.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab010_Supplementary_Data Click here for additional data file. | LABETALOL\LABETALOL HYDROCHLORIDE, METOPROLOL | DrugsGivenReaction | CC BY-NC | 33693306 | 20,151,132 | 2021-03 |
What was the administration route of drug 'LABETALOL\LABETALOL HYDROCHLORIDE'? | Managing asymptomatic severe rheumatic mitral stenosis in pregnancy: a case report.
Rheumatic heart disease (RHD) is a disease of disparity most prevalent in developing countries and among immigrant populations. Mitral stenosis (MS) is a common sequalae of RHD and affects females disproportionately more than males. Rheumatic MS remains a significant management challenge as severe MS is usually poorly tolerated in pregnancy due to haemodynamic changes and increased cardiovascular demands of progressing pregnancy. Pregnancy remains contraindicated in current management guidelines based on expert consensus, due to a paucity of evidence-based literature.
A 28-year-old aboriginal woman with known severe MS was found to be pregnant during routine health review, despite contraceptive efforts. Echocardiography demonstrated mean mitral valve (MV) gradient 14 mmHg; stress echocardiography demonstrated increased MV gradient 28-32 mmHg at peak exercise and post-exercise pulmonary artery pressure 56 + 3 mmHg with marked dynamic D-shaped septal flattening. Left ventricular systolic function remained preserved. She remained remarkably asymptomatic and underwent successful elective induction of labour at 34 weeks. Postpartum, she remained euvolaemic despite worsening MV gradients and new atrial fibrillation (AF). She subsequently underwent balloon mitral valvuloplasty with good result.
Severe rheumatic MS in pregnancy carries significant morbidity and mortality, due to an already fragile predisposition towards heart failure development compounded by altered haemodynamics. Pregnancy avoidance and valvular intervention prior to conception or in the second trimester remain the mainstay of MS management; however, we present an encouraging case of successful near-term pregnancy with minimal complications in a medically managed asymptomatic patient with critical MS, who subsequently underwent valvular intervention post-partum.
Learning points
There is limited information regarding the management of severe mitral stenosis (MS) in women of childbearing age or who are pregnant, particularly if they remain asymptomatic.
Serial echocardiography combined with stress testing and physiological assessment for surveillance of mitral valve gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, and timing of percutaneous balloon mitral valvuloplasty (BMV).
Percutaneous BMV may be safely deferred until postpartum in women with severe MS who remain asymptomatic, to minimize procedural risks for mother and developing foetus.
Introduction
Left-sided stenotic valvulopathies, including mitral stenosis (MS), remain a feared entity in pregnancy due to the effects of altered physiology including increased intravascular volume, cardiac output and heart rate, and decreased systemic vascular resistance and systolic blood pressure1 which increases MS complication risks. Maternal complications include pulmonary oedema, arrhythmias, and increased mortality, whilst foetal complications include preterm delivery, intrauterine growth restriction, and foetal death.1
The risk of developing heart failure corresponds with MS severity.2 Severe MS is usually poorly tolerated in pregnancy, with 67% of women developing peripartum heart failure even if previously asymptomatic.2–4 This is contributed to by increased heart rates antepartum, resulting in shortened diastolic filling time, increased left atrial pressure, and pulmonary venous pressures predisposing to heart failure.4 Pregnancy is contraindicated in current guidelines, which recommend percutaneous valvular intervention in women with moderate or severe MS contemplating pregnancy5 (Figure 1).
Figure 1 Managing severe rheumatic mitral stenosis in pregnancy.
We present our management of a remarkably asymptomatic patient with critical MS, who presented 13 weeks antepartum despite contraceptive efforts and without preconception valve intervention. The valvular intervention occurred postpartum, with good outcomes for both mother and child.
Timeline
Case presentation
A 28-year-old aboriginal Australian woman from a remote community with known severe MS was found to be 13 weeks pregnant despite contraceptive depot injections, after presenting for routine review at the local community clinic.
She had a previous episode of acute rheumatic fever aged 10. She had been adherent with standard secondary prophylaxis regimen since but subsequently developed severe mitral stenosis necessitating balloon mitral valvuloplasty (BMV) aged 14. Prior to pregnancy, her last echocardiogram in 2018 demonstrated severe rheumatic MS with mean pressure gradient (mPG) 17 mmHg, mitral valve area (MVA) 0.9 cm2, and mild pulmonary hypertension with estimated pulmonary artery pressure (EPAP) 30 mmHg + right atrial pressure (RAP) 3 mmHg. Left ventricular systolic function was preserved. She remained clinically asymptomatic and was therefore managed conservatively. Additionally, she received pregnancy-avoidance counselling and agreed to commence 3-monthly contraceptive depot injections. She did not have other medical conditions or regular medications.
Due to the cultural significance of pregnancy within her community, she elected to continue her pregnancy fully cognisant of the increased risks of adverse outcomes secondary to her valvulopathy. She was subsequently referred for Cardiology Specialist input.
She remained remarkably asymptomatic despite critical MS. Physical examination demonstrated dual heart sounds with an additional soft diastolic murmur. There was no evidence of pulmonary congestion of peripheral oedema. Her NTproBNP level was 136 ng/L. She had mild normocytic anaemia (Hb 106 g/L; mean cell volume 85.8 fL); electrolytes and creatinine levels were normal (sodium 135 mmol/L, potassium 3.8 mmol/L, creatinine 54 µmol/L, estimated glomerular filtrate rate >90 mL/min/1.73 m2). Transthoracic echocardiography (TTE) at 13 weeks antepartum demonstrated a doming hockey stick appearance of the anterior mitral valve leaflet, thickened immobile posterior mitral leaflet with markedly restricted excursion resulting in severe mitral stenosis (mPG 14 mmHg), mitral valve area 0.4 cm2, severely dilated left atrium (indexed volume 50 mL/m2), mild pulmonary hypertension (EPAP 34 + 3 mmHg). Stress echocardiogram performed at 20 weeks antepartum demonstrated mitral valve (MV) mPG 28–32 mmHg at peak exercise, and post-exercise EPAP 56 + 3 mmHg with development of D-shaped septal flattening (Figure 2). She did not desaturate during this test. Given her minimal symptoms, she was successfully managed in a culturally sensitive manner in her remote community until the early third trimester, where she was electively admitted to a local tertiary hospital before transfer to a tertiary centre with cardiothoracic services for valve intervention prior to delivery.
Figure 2 Exercise stress echocardiogram demonstrating (A) left ventricular at rest and (B) marked septal D-shape flattening with peak exercise.
Serial TTEs during antepartum demonstrated critical but stable MV gradients (mPG 19–21 mmHg; Figure 3). She was also commenced on beta-blocker therapy to minimize maternal tachycardia. She remained clinically and haemodynamically stable until the planned induction of labour at 34 weeks. This was subsequently converted to caesarean section due to abnormal foetal cardiotocography, with the delivery of a healthy male baby.
Figure 3 Transthoracic echocardiogram demonstrating (A) severe mitral stenosis and (B) pulmonary hypertension.
Beta-blocker therapy was held for 24 h post-partum. The reason for this was unclear however was re-initiated together with digoxin due to worsening MV gradients (mPG 29 mmHg), EPAP 57 ± 3 mmHg (Figure 4), and development of palpitations secondary to new atrial fibrillation (AF) Day 2 postpartum. She remained clinically euvolaemic, and following consultation with her treating teams, she underwent elective BMV Day 8 postpartum with improved MV gradients and MVA (Figure 5). She remained well and was discharged Day 10 post-partum post-contraceptive implantation. She remained well on telephone review Day 2 post-discharge, prior to return to her local community.
Figure 4 First postpartum transthoracic echocardiogram demonstrating (A) critical mitral stenosis and (B) pulmonary hypertension.
Figure 5 Balloon inflation during balloon mitral valvuloplasty. (A) Distal balloon inflation. (B) Inflation of proximal and middle balloon, with waist in mid-portion of balloon demonstrating mitral stenosis. (C) Full balloon inflation. Post-balloon mitral valvuloplasty transthoracic echocardiogram demonstrating (D) moderate mitral stenosis and (E) mild pulmonary hypertension.
Discussion
Whilst not common in developed countries, MS accounts for 9.5% of all valvular heart disease in Europe. Rheumatic heart disease (RHD) remains the most common aetiology.6 In Australia, RHD is a striking disease of disparity, where 89% of affected Australians identify as Aboriginal or Torres Strait Islander, representing a rate 6.6 times higher than non-Indigenous Australians.7 47% of Aboriginal or Torres Strait Islanders affected are aged under 20 years.7 Women account for 61% of the total indigenous RHD burden,7 attracting the greatest risk of poor outcomes, especially during pregnancy.
Pregnancy remains a World Health Organisation (WHO) Class IV contraindication in severe MS, due to maternal and foetal morbidity and mortality;5 however, there is a paucity of information regarding the management of severe MS in women of childbearing age or who are pregnant, particularly if they remain asymptomatic. The current guidelines are based on expert consensus which strongly recommends pregnancy avoidance or consideration of pregnancy termination, and do not address or acknowledge cultural sensitivities, varying levels of medical literacy or socioeconomic constraints of patient populations where RHD is likely more prevalent. Management of an already pregnant patient focuses on a combination of pharmacological agents including beta-blockers and diuretics, and clinical monitoring to identify the development of intervention indications.5,8 Percutaneous valvular intervention is recommended preconception. The intrapartum intervention has been reported but only in persistently symptomatic patients between second and third trimesters9 to consider organogenesis of the foetus. This does not take into account the hyperactive mammary tissue exposed to radiation, or the longer-term risk of childhood malignancy. Current guidelines do not account for many of these issues, or the timing and utility of serial echocardiographic assessments to guide percutaneous intervention as pregnancy develops.
This case demonstrates a number of important points. Achievement of pregnancy avoidance may not always be achieved despite its prescription. Serial echocardiography in combination with stress testing and physiological assessment for the surveillance of MV gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, as well as the timing of percutaneous BMV. We have also demonstrated the safe and successful deferral of percutaneous BMV until post-partum in asymptomatic patients, protecting both the developing foetus and also maternal mammary tissue which remains increasingly active postpartum from potentially harmful radiation.
Our case highlights the importance of patient-specific care and that further understanding of severe MS management in women of childbearing age and intrapartum is required to improve maternal and foetal outcomes.
Lead author biography
Joanne M. H. Eng-Frost is a Cardiology Advanced Trainee at Flinders Medical Centre in Adelaide, Australia. She completed a Bachelor of Science (Biomedical Science) degree with Honours in Physiology at the University of Adelaide, Australia before earning a Doctor of Medicine (MD) degree at Flinders University, Australia. Her clinical interests include structural heart disease and interventional cardiology.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab010_Supplementary_Data Click here for additional data file. | Transplacental | DrugAdministrationRoute | CC BY-NC | 33693306 | 20,151,132 | 2021-03 |
What was the administration route of drug 'METOPROLOL'? | Managing asymptomatic severe rheumatic mitral stenosis in pregnancy: a case report.
Rheumatic heart disease (RHD) is a disease of disparity most prevalent in developing countries and among immigrant populations. Mitral stenosis (MS) is a common sequalae of RHD and affects females disproportionately more than males. Rheumatic MS remains a significant management challenge as severe MS is usually poorly tolerated in pregnancy due to haemodynamic changes and increased cardiovascular demands of progressing pregnancy. Pregnancy remains contraindicated in current management guidelines based on expert consensus, due to a paucity of evidence-based literature.
A 28-year-old aboriginal woman with known severe MS was found to be pregnant during routine health review, despite contraceptive efforts. Echocardiography demonstrated mean mitral valve (MV) gradient 14 mmHg; stress echocardiography demonstrated increased MV gradient 28-32 mmHg at peak exercise and post-exercise pulmonary artery pressure 56 + 3 mmHg with marked dynamic D-shaped septal flattening. Left ventricular systolic function remained preserved. She remained remarkably asymptomatic and underwent successful elective induction of labour at 34 weeks. Postpartum, she remained euvolaemic despite worsening MV gradients and new atrial fibrillation (AF). She subsequently underwent balloon mitral valvuloplasty with good result.
Severe rheumatic MS in pregnancy carries significant morbidity and mortality, due to an already fragile predisposition towards heart failure development compounded by altered haemodynamics. Pregnancy avoidance and valvular intervention prior to conception or in the second trimester remain the mainstay of MS management; however, we present an encouraging case of successful near-term pregnancy with minimal complications in a medically managed asymptomatic patient with critical MS, who subsequently underwent valvular intervention post-partum.
Learning points
There is limited information regarding the management of severe mitral stenosis (MS) in women of childbearing age or who are pregnant, particularly if they remain asymptomatic.
Serial echocardiography combined with stress testing and physiological assessment for surveillance of mitral valve gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, and timing of percutaneous balloon mitral valvuloplasty (BMV).
Percutaneous BMV may be safely deferred until postpartum in women with severe MS who remain asymptomatic, to minimize procedural risks for mother and developing foetus.
Introduction
Left-sided stenotic valvulopathies, including mitral stenosis (MS), remain a feared entity in pregnancy due to the effects of altered physiology including increased intravascular volume, cardiac output and heart rate, and decreased systemic vascular resistance and systolic blood pressure1 which increases MS complication risks. Maternal complications include pulmonary oedema, arrhythmias, and increased mortality, whilst foetal complications include preterm delivery, intrauterine growth restriction, and foetal death.1
The risk of developing heart failure corresponds with MS severity.2 Severe MS is usually poorly tolerated in pregnancy, with 67% of women developing peripartum heart failure even if previously asymptomatic.2–4 This is contributed to by increased heart rates antepartum, resulting in shortened diastolic filling time, increased left atrial pressure, and pulmonary venous pressures predisposing to heart failure.4 Pregnancy is contraindicated in current guidelines, which recommend percutaneous valvular intervention in women with moderate or severe MS contemplating pregnancy5 (Figure 1).
Figure 1 Managing severe rheumatic mitral stenosis in pregnancy.
We present our management of a remarkably asymptomatic patient with critical MS, who presented 13 weeks antepartum despite contraceptive efforts and without preconception valve intervention. The valvular intervention occurred postpartum, with good outcomes for both mother and child.
Timeline
Case presentation
A 28-year-old aboriginal Australian woman from a remote community with known severe MS was found to be 13 weeks pregnant despite contraceptive depot injections, after presenting for routine review at the local community clinic.
She had a previous episode of acute rheumatic fever aged 10. She had been adherent with standard secondary prophylaxis regimen since but subsequently developed severe mitral stenosis necessitating balloon mitral valvuloplasty (BMV) aged 14. Prior to pregnancy, her last echocardiogram in 2018 demonstrated severe rheumatic MS with mean pressure gradient (mPG) 17 mmHg, mitral valve area (MVA) 0.9 cm2, and mild pulmonary hypertension with estimated pulmonary artery pressure (EPAP) 30 mmHg + right atrial pressure (RAP) 3 mmHg. Left ventricular systolic function was preserved. She remained clinically asymptomatic and was therefore managed conservatively. Additionally, she received pregnancy-avoidance counselling and agreed to commence 3-monthly contraceptive depot injections. She did not have other medical conditions or regular medications.
Due to the cultural significance of pregnancy within her community, she elected to continue her pregnancy fully cognisant of the increased risks of adverse outcomes secondary to her valvulopathy. She was subsequently referred for Cardiology Specialist input.
She remained remarkably asymptomatic despite critical MS. Physical examination demonstrated dual heart sounds with an additional soft diastolic murmur. There was no evidence of pulmonary congestion of peripheral oedema. Her NTproBNP level was 136 ng/L. She had mild normocytic anaemia (Hb 106 g/L; mean cell volume 85.8 fL); electrolytes and creatinine levels were normal (sodium 135 mmol/L, potassium 3.8 mmol/L, creatinine 54 µmol/L, estimated glomerular filtrate rate >90 mL/min/1.73 m2). Transthoracic echocardiography (TTE) at 13 weeks antepartum demonstrated a doming hockey stick appearance of the anterior mitral valve leaflet, thickened immobile posterior mitral leaflet with markedly restricted excursion resulting in severe mitral stenosis (mPG 14 mmHg), mitral valve area 0.4 cm2, severely dilated left atrium (indexed volume 50 mL/m2), mild pulmonary hypertension (EPAP 34 + 3 mmHg). Stress echocardiogram performed at 20 weeks antepartum demonstrated mitral valve (MV) mPG 28–32 mmHg at peak exercise, and post-exercise EPAP 56 + 3 mmHg with development of D-shaped septal flattening (Figure 2). She did not desaturate during this test. Given her minimal symptoms, she was successfully managed in a culturally sensitive manner in her remote community until the early third trimester, where she was electively admitted to a local tertiary hospital before transfer to a tertiary centre with cardiothoracic services for valve intervention prior to delivery.
Figure 2 Exercise stress echocardiogram demonstrating (A) left ventricular at rest and (B) marked septal D-shape flattening with peak exercise.
Serial TTEs during antepartum demonstrated critical but stable MV gradients (mPG 19–21 mmHg; Figure 3). She was also commenced on beta-blocker therapy to minimize maternal tachycardia. She remained clinically and haemodynamically stable until the planned induction of labour at 34 weeks. This was subsequently converted to caesarean section due to abnormal foetal cardiotocography, with the delivery of a healthy male baby.
Figure 3 Transthoracic echocardiogram demonstrating (A) severe mitral stenosis and (B) pulmonary hypertension.
Beta-blocker therapy was held for 24 h post-partum. The reason for this was unclear however was re-initiated together with digoxin due to worsening MV gradients (mPG 29 mmHg), EPAP 57 ± 3 mmHg (Figure 4), and development of palpitations secondary to new atrial fibrillation (AF) Day 2 postpartum. She remained clinically euvolaemic, and following consultation with her treating teams, she underwent elective BMV Day 8 postpartum with improved MV gradients and MVA (Figure 5). She remained well and was discharged Day 10 post-partum post-contraceptive implantation. She remained well on telephone review Day 2 post-discharge, prior to return to her local community.
Figure 4 First postpartum transthoracic echocardiogram demonstrating (A) critical mitral stenosis and (B) pulmonary hypertension.
Figure 5 Balloon inflation during balloon mitral valvuloplasty. (A) Distal balloon inflation. (B) Inflation of proximal and middle balloon, with waist in mid-portion of balloon demonstrating mitral stenosis. (C) Full balloon inflation. Post-balloon mitral valvuloplasty transthoracic echocardiogram demonstrating (D) moderate mitral stenosis and (E) mild pulmonary hypertension.
Discussion
Whilst not common in developed countries, MS accounts for 9.5% of all valvular heart disease in Europe. Rheumatic heart disease (RHD) remains the most common aetiology.6 In Australia, RHD is a striking disease of disparity, where 89% of affected Australians identify as Aboriginal or Torres Strait Islander, representing a rate 6.6 times higher than non-Indigenous Australians.7 47% of Aboriginal or Torres Strait Islanders affected are aged under 20 years.7 Women account for 61% of the total indigenous RHD burden,7 attracting the greatest risk of poor outcomes, especially during pregnancy.
Pregnancy remains a World Health Organisation (WHO) Class IV contraindication in severe MS, due to maternal and foetal morbidity and mortality;5 however, there is a paucity of information regarding the management of severe MS in women of childbearing age or who are pregnant, particularly if they remain asymptomatic. The current guidelines are based on expert consensus which strongly recommends pregnancy avoidance or consideration of pregnancy termination, and do not address or acknowledge cultural sensitivities, varying levels of medical literacy or socioeconomic constraints of patient populations where RHD is likely more prevalent. Management of an already pregnant patient focuses on a combination of pharmacological agents including beta-blockers and diuretics, and clinical monitoring to identify the development of intervention indications.5,8 Percutaneous valvular intervention is recommended preconception. The intrapartum intervention has been reported but only in persistently symptomatic patients between second and third trimesters9 to consider organogenesis of the foetus. This does not take into account the hyperactive mammary tissue exposed to radiation, or the longer-term risk of childhood malignancy. Current guidelines do not account for many of these issues, or the timing and utility of serial echocardiographic assessments to guide percutaneous intervention as pregnancy develops.
This case demonstrates a number of important points. Achievement of pregnancy avoidance may not always be achieved despite its prescription. Serial echocardiography in combination with stress testing and physiological assessment for the surveillance of MV gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, as well as the timing of percutaneous BMV. We have also demonstrated the safe and successful deferral of percutaneous BMV until post-partum in asymptomatic patients, protecting both the developing foetus and also maternal mammary tissue which remains increasingly active postpartum from potentially harmful radiation.
Our case highlights the importance of patient-specific care and that further understanding of severe MS management in women of childbearing age and intrapartum is required to improve maternal and foetal outcomes.
Lead author biography
Joanne M. H. Eng-Frost is a Cardiology Advanced Trainee at Flinders Medical Centre in Adelaide, Australia. She completed a Bachelor of Science (Biomedical Science) degree with Honours in Physiology at the University of Adelaide, Australia before earning a Doctor of Medicine (MD) degree at Flinders University, Australia. Her clinical interests include structural heart disease and interventional cardiology.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab010_Supplementary_Data Click here for additional data file. | Transplacental | DrugAdministrationRoute | CC BY-NC | 33693306 | 20,151,132 | 2021-03 |
What was the dosage of drug 'LABETALOL\LABETALOL HYDROCHLORIDE'? | Managing asymptomatic severe rheumatic mitral stenosis in pregnancy: a case report.
Rheumatic heart disease (RHD) is a disease of disparity most prevalent in developing countries and among immigrant populations. Mitral stenosis (MS) is a common sequalae of RHD and affects females disproportionately more than males. Rheumatic MS remains a significant management challenge as severe MS is usually poorly tolerated in pregnancy due to haemodynamic changes and increased cardiovascular demands of progressing pregnancy. Pregnancy remains contraindicated in current management guidelines based on expert consensus, due to a paucity of evidence-based literature.
A 28-year-old aboriginal woman with known severe MS was found to be pregnant during routine health review, despite contraceptive efforts. Echocardiography demonstrated mean mitral valve (MV) gradient 14 mmHg; stress echocardiography demonstrated increased MV gradient 28-32 mmHg at peak exercise and post-exercise pulmonary artery pressure 56 + 3 mmHg with marked dynamic D-shaped septal flattening. Left ventricular systolic function remained preserved. She remained remarkably asymptomatic and underwent successful elective induction of labour at 34 weeks. Postpartum, she remained euvolaemic despite worsening MV gradients and new atrial fibrillation (AF). She subsequently underwent balloon mitral valvuloplasty with good result.
Severe rheumatic MS in pregnancy carries significant morbidity and mortality, due to an already fragile predisposition towards heart failure development compounded by altered haemodynamics. Pregnancy avoidance and valvular intervention prior to conception or in the second trimester remain the mainstay of MS management; however, we present an encouraging case of successful near-term pregnancy with minimal complications in a medically managed asymptomatic patient with critical MS, who subsequently underwent valvular intervention post-partum.
Learning points
There is limited information regarding the management of severe mitral stenosis (MS) in women of childbearing age or who are pregnant, particularly if they remain asymptomatic.
Serial echocardiography combined with stress testing and physiological assessment for surveillance of mitral valve gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, and timing of percutaneous balloon mitral valvuloplasty (BMV).
Percutaneous BMV may be safely deferred until postpartum in women with severe MS who remain asymptomatic, to minimize procedural risks for mother and developing foetus.
Introduction
Left-sided stenotic valvulopathies, including mitral stenosis (MS), remain a feared entity in pregnancy due to the effects of altered physiology including increased intravascular volume, cardiac output and heart rate, and decreased systemic vascular resistance and systolic blood pressure1 which increases MS complication risks. Maternal complications include pulmonary oedema, arrhythmias, and increased mortality, whilst foetal complications include preterm delivery, intrauterine growth restriction, and foetal death.1
The risk of developing heart failure corresponds with MS severity.2 Severe MS is usually poorly tolerated in pregnancy, with 67% of women developing peripartum heart failure even if previously asymptomatic.2–4 This is contributed to by increased heart rates antepartum, resulting in shortened diastolic filling time, increased left atrial pressure, and pulmonary venous pressures predisposing to heart failure.4 Pregnancy is contraindicated in current guidelines, which recommend percutaneous valvular intervention in women with moderate or severe MS contemplating pregnancy5 (Figure 1).
Figure 1 Managing severe rheumatic mitral stenosis in pregnancy.
We present our management of a remarkably asymptomatic patient with critical MS, who presented 13 weeks antepartum despite contraceptive efforts and without preconception valve intervention. The valvular intervention occurred postpartum, with good outcomes for both mother and child.
Timeline
Case presentation
A 28-year-old aboriginal Australian woman from a remote community with known severe MS was found to be 13 weeks pregnant despite contraceptive depot injections, after presenting for routine review at the local community clinic.
She had a previous episode of acute rheumatic fever aged 10. She had been adherent with standard secondary prophylaxis regimen since but subsequently developed severe mitral stenosis necessitating balloon mitral valvuloplasty (BMV) aged 14. Prior to pregnancy, her last echocardiogram in 2018 demonstrated severe rheumatic MS with mean pressure gradient (mPG) 17 mmHg, mitral valve area (MVA) 0.9 cm2, and mild pulmonary hypertension with estimated pulmonary artery pressure (EPAP) 30 mmHg + right atrial pressure (RAP) 3 mmHg. Left ventricular systolic function was preserved. She remained clinically asymptomatic and was therefore managed conservatively. Additionally, she received pregnancy-avoidance counselling and agreed to commence 3-monthly contraceptive depot injections. She did not have other medical conditions or regular medications.
Due to the cultural significance of pregnancy within her community, she elected to continue her pregnancy fully cognisant of the increased risks of adverse outcomes secondary to her valvulopathy. She was subsequently referred for Cardiology Specialist input.
She remained remarkably asymptomatic despite critical MS. Physical examination demonstrated dual heart sounds with an additional soft diastolic murmur. There was no evidence of pulmonary congestion of peripheral oedema. Her NTproBNP level was 136 ng/L. She had mild normocytic anaemia (Hb 106 g/L; mean cell volume 85.8 fL); electrolytes and creatinine levels were normal (sodium 135 mmol/L, potassium 3.8 mmol/L, creatinine 54 µmol/L, estimated glomerular filtrate rate >90 mL/min/1.73 m2). Transthoracic echocardiography (TTE) at 13 weeks antepartum demonstrated a doming hockey stick appearance of the anterior mitral valve leaflet, thickened immobile posterior mitral leaflet with markedly restricted excursion resulting in severe mitral stenosis (mPG 14 mmHg), mitral valve area 0.4 cm2, severely dilated left atrium (indexed volume 50 mL/m2), mild pulmonary hypertension (EPAP 34 + 3 mmHg). Stress echocardiogram performed at 20 weeks antepartum demonstrated mitral valve (MV) mPG 28–32 mmHg at peak exercise, and post-exercise EPAP 56 + 3 mmHg with development of D-shaped septal flattening (Figure 2). She did not desaturate during this test. Given her minimal symptoms, she was successfully managed in a culturally sensitive manner in her remote community until the early third trimester, where she was electively admitted to a local tertiary hospital before transfer to a tertiary centre with cardiothoracic services for valve intervention prior to delivery.
Figure 2 Exercise stress echocardiogram demonstrating (A) left ventricular at rest and (B) marked septal D-shape flattening with peak exercise.
Serial TTEs during antepartum demonstrated critical but stable MV gradients (mPG 19–21 mmHg; Figure 3). She was also commenced on beta-blocker therapy to minimize maternal tachycardia. She remained clinically and haemodynamically stable until the planned induction of labour at 34 weeks. This was subsequently converted to caesarean section due to abnormal foetal cardiotocography, with the delivery of a healthy male baby.
Figure 3 Transthoracic echocardiogram demonstrating (A) severe mitral stenosis and (B) pulmonary hypertension.
Beta-blocker therapy was held for 24 h post-partum. The reason for this was unclear however was re-initiated together with digoxin due to worsening MV gradients (mPG 29 mmHg), EPAP 57 ± 3 mmHg (Figure 4), and development of palpitations secondary to new atrial fibrillation (AF) Day 2 postpartum. She remained clinically euvolaemic, and following consultation with her treating teams, she underwent elective BMV Day 8 postpartum with improved MV gradients and MVA (Figure 5). She remained well and was discharged Day 10 post-partum post-contraceptive implantation. She remained well on telephone review Day 2 post-discharge, prior to return to her local community.
Figure 4 First postpartum transthoracic echocardiogram demonstrating (A) critical mitral stenosis and (B) pulmonary hypertension.
Figure 5 Balloon inflation during balloon mitral valvuloplasty. (A) Distal balloon inflation. (B) Inflation of proximal and middle balloon, with waist in mid-portion of balloon demonstrating mitral stenosis. (C) Full balloon inflation. Post-balloon mitral valvuloplasty transthoracic echocardiogram demonstrating (D) moderate mitral stenosis and (E) mild pulmonary hypertension.
Discussion
Whilst not common in developed countries, MS accounts for 9.5% of all valvular heart disease in Europe. Rheumatic heart disease (RHD) remains the most common aetiology.6 In Australia, RHD is a striking disease of disparity, where 89% of affected Australians identify as Aboriginal or Torres Strait Islander, representing a rate 6.6 times higher than non-Indigenous Australians.7 47% of Aboriginal or Torres Strait Islanders affected are aged under 20 years.7 Women account for 61% of the total indigenous RHD burden,7 attracting the greatest risk of poor outcomes, especially during pregnancy.
Pregnancy remains a World Health Organisation (WHO) Class IV contraindication in severe MS, due to maternal and foetal morbidity and mortality;5 however, there is a paucity of information regarding the management of severe MS in women of childbearing age or who are pregnant, particularly if they remain asymptomatic. The current guidelines are based on expert consensus which strongly recommends pregnancy avoidance or consideration of pregnancy termination, and do not address or acknowledge cultural sensitivities, varying levels of medical literacy or socioeconomic constraints of patient populations where RHD is likely more prevalent. Management of an already pregnant patient focuses on a combination of pharmacological agents including beta-blockers and diuretics, and clinical monitoring to identify the development of intervention indications.5,8 Percutaneous valvular intervention is recommended preconception. The intrapartum intervention has been reported but only in persistently symptomatic patients between second and third trimesters9 to consider organogenesis of the foetus. This does not take into account the hyperactive mammary tissue exposed to radiation, or the longer-term risk of childhood malignancy. Current guidelines do not account for many of these issues, or the timing and utility of serial echocardiographic assessments to guide percutaneous intervention as pregnancy develops.
This case demonstrates a number of important points. Achievement of pregnancy avoidance may not always be achieved despite its prescription. Serial echocardiography in combination with stress testing and physiological assessment for the surveillance of MV gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, as well as the timing of percutaneous BMV. We have also demonstrated the safe and successful deferral of percutaneous BMV until post-partum in asymptomatic patients, protecting both the developing foetus and also maternal mammary tissue which remains increasingly active postpartum from potentially harmful radiation.
Our case highlights the importance of patient-specific care and that further understanding of severe MS management in women of childbearing age and intrapartum is required to improve maternal and foetal outcomes.
Lead author biography
Joanne M. H. Eng-Frost is a Cardiology Advanced Trainee at Flinders Medical Centre in Adelaide, Australia. She completed a Bachelor of Science (Biomedical Science) degree with Honours in Physiology at the University of Adelaide, Australia before earning a Doctor of Medicine (MD) degree at Flinders University, Australia. Her clinical interests include structural heart disease and interventional cardiology.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab010_Supplementary_Data Click here for additional data file. | MATERNAL DOSE AT EXPOSURE: 50 MG BID | DrugDosageText | CC BY-NC | 33693306 | 20,151,132 | 2021-03 |
What was the dosage of drug 'METOPROLOL'? | Managing asymptomatic severe rheumatic mitral stenosis in pregnancy: a case report.
Rheumatic heart disease (RHD) is a disease of disparity most prevalent in developing countries and among immigrant populations. Mitral stenosis (MS) is a common sequalae of RHD and affects females disproportionately more than males. Rheumatic MS remains a significant management challenge as severe MS is usually poorly tolerated in pregnancy due to haemodynamic changes and increased cardiovascular demands of progressing pregnancy. Pregnancy remains contraindicated in current management guidelines based on expert consensus, due to a paucity of evidence-based literature.
A 28-year-old aboriginal woman with known severe MS was found to be pregnant during routine health review, despite contraceptive efforts. Echocardiography demonstrated mean mitral valve (MV) gradient 14 mmHg; stress echocardiography demonstrated increased MV gradient 28-32 mmHg at peak exercise and post-exercise pulmonary artery pressure 56 + 3 mmHg with marked dynamic D-shaped septal flattening. Left ventricular systolic function remained preserved. She remained remarkably asymptomatic and underwent successful elective induction of labour at 34 weeks. Postpartum, she remained euvolaemic despite worsening MV gradients and new atrial fibrillation (AF). She subsequently underwent balloon mitral valvuloplasty with good result.
Severe rheumatic MS in pregnancy carries significant morbidity and mortality, due to an already fragile predisposition towards heart failure development compounded by altered haemodynamics. Pregnancy avoidance and valvular intervention prior to conception or in the second trimester remain the mainstay of MS management; however, we present an encouraging case of successful near-term pregnancy with minimal complications in a medically managed asymptomatic patient with critical MS, who subsequently underwent valvular intervention post-partum.
Learning points
There is limited information regarding the management of severe mitral stenosis (MS) in women of childbearing age or who are pregnant, particularly if they remain asymptomatic.
Serial echocardiography combined with stress testing and physiological assessment for surveillance of mitral valve gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, and timing of percutaneous balloon mitral valvuloplasty (BMV).
Percutaneous BMV may be safely deferred until postpartum in women with severe MS who remain asymptomatic, to minimize procedural risks for mother and developing foetus.
Introduction
Left-sided stenotic valvulopathies, including mitral stenosis (MS), remain a feared entity in pregnancy due to the effects of altered physiology including increased intravascular volume, cardiac output and heart rate, and decreased systemic vascular resistance and systolic blood pressure1 which increases MS complication risks. Maternal complications include pulmonary oedema, arrhythmias, and increased mortality, whilst foetal complications include preterm delivery, intrauterine growth restriction, and foetal death.1
The risk of developing heart failure corresponds with MS severity.2 Severe MS is usually poorly tolerated in pregnancy, with 67% of women developing peripartum heart failure even if previously asymptomatic.2–4 This is contributed to by increased heart rates antepartum, resulting in shortened diastolic filling time, increased left atrial pressure, and pulmonary venous pressures predisposing to heart failure.4 Pregnancy is contraindicated in current guidelines, which recommend percutaneous valvular intervention in women with moderate or severe MS contemplating pregnancy5 (Figure 1).
Figure 1 Managing severe rheumatic mitral stenosis in pregnancy.
We present our management of a remarkably asymptomatic patient with critical MS, who presented 13 weeks antepartum despite contraceptive efforts and without preconception valve intervention. The valvular intervention occurred postpartum, with good outcomes for both mother and child.
Timeline
Case presentation
A 28-year-old aboriginal Australian woman from a remote community with known severe MS was found to be 13 weeks pregnant despite contraceptive depot injections, after presenting for routine review at the local community clinic.
She had a previous episode of acute rheumatic fever aged 10. She had been adherent with standard secondary prophylaxis regimen since but subsequently developed severe mitral stenosis necessitating balloon mitral valvuloplasty (BMV) aged 14. Prior to pregnancy, her last echocardiogram in 2018 demonstrated severe rheumatic MS with mean pressure gradient (mPG) 17 mmHg, mitral valve area (MVA) 0.9 cm2, and mild pulmonary hypertension with estimated pulmonary artery pressure (EPAP) 30 mmHg + right atrial pressure (RAP) 3 mmHg. Left ventricular systolic function was preserved. She remained clinically asymptomatic and was therefore managed conservatively. Additionally, she received pregnancy-avoidance counselling and agreed to commence 3-monthly contraceptive depot injections. She did not have other medical conditions or regular medications.
Due to the cultural significance of pregnancy within her community, she elected to continue her pregnancy fully cognisant of the increased risks of adverse outcomes secondary to her valvulopathy. She was subsequently referred for Cardiology Specialist input.
She remained remarkably asymptomatic despite critical MS. Physical examination demonstrated dual heart sounds with an additional soft diastolic murmur. There was no evidence of pulmonary congestion of peripheral oedema. Her NTproBNP level was 136 ng/L. She had mild normocytic anaemia (Hb 106 g/L; mean cell volume 85.8 fL); electrolytes and creatinine levels were normal (sodium 135 mmol/L, potassium 3.8 mmol/L, creatinine 54 µmol/L, estimated glomerular filtrate rate >90 mL/min/1.73 m2). Transthoracic echocardiography (TTE) at 13 weeks antepartum demonstrated a doming hockey stick appearance of the anterior mitral valve leaflet, thickened immobile posterior mitral leaflet with markedly restricted excursion resulting in severe mitral stenosis (mPG 14 mmHg), mitral valve area 0.4 cm2, severely dilated left atrium (indexed volume 50 mL/m2), mild pulmonary hypertension (EPAP 34 + 3 mmHg). Stress echocardiogram performed at 20 weeks antepartum demonstrated mitral valve (MV) mPG 28–32 mmHg at peak exercise, and post-exercise EPAP 56 + 3 mmHg with development of D-shaped septal flattening (Figure 2). She did not desaturate during this test. Given her minimal symptoms, she was successfully managed in a culturally sensitive manner in her remote community until the early third trimester, where she was electively admitted to a local tertiary hospital before transfer to a tertiary centre with cardiothoracic services for valve intervention prior to delivery.
Figure 2 Exercise stress echocardiogram demonstrating (A) left ventricular at rest and (B) marked septal D-shape flattening with peak exercise.
Serial TTEs during antepartum demonstrated critical but stable MV gradients (mPG 19–21 mmHg; Figure 3). She was also commenced on beta-blocker therapy to minimize maternal tachycardia. She remained clinically and haemodynamically stable until the planned induction of labour at 34 weeks. This was subsequently converted to caesarean section due to abnormal foetal cardiotocography, with the delivery of a healthy male baby.
Figure 3 Transthoracic echocardiogram demonstrating (A) severe mitral stenosis and (B) pulmonary hypertension.
Beta-blocker therapy was held for 24 h post-partum. The reason for this was unclear however was re-initiated together with digoxin due to worsening MV gradients (mPG 29 mmHg), EPAP 57 ± 3 mmHg (Figure 4), and development of palpitations secondary to new atrial fibrillation (AF) Day 2 postpartum. She remained clinically euvolaemic, and following consultation with her treating teams, she underwent elective BMV Day 8 postpartum with improved MV gradients and MVA (Figure 5). She remained well and was discharged Day 10 post-partum post-contraceptive implantation. She remained well on telephone review Day 2 post-discharge, prior to return to her local community.
Figure 4 First postpartum transthoracic echocardiogram demonstrating (A) critical mitral stenosis and (B) pulmonary hypertension.
Figure 5 Balloon inflation during balloon mitral valvuloplasty. (A) Distal balloon inflation. (B) Inflation of proximal and middle balloon, with waist in mid-portion of balloon demonstrating mitral stenosis. (C) Full balloon inflation. Post-balloon mitral valvuloplasty transthoracic echocardiogram demonstrating (D) moderate mitral stenosis and (E) mild pulmonary hypertension.
Discussion
Whilst not common in developed countries, MS accounts for 9.5% of all valvular heart disease in Europe. Rheumatic heart disease (RHD) remains the most common aetiology.6 In Australia, RHD is a striking disease of disparity, where 89% of affected Australians identify as Aboriginal or Torres Strait Islander, representing a rate 6.6 times higher than non-Indigenous Australians.7 47% of Aboriginal or Torres Strait Islanders affected are aged under 20 years.7 Women account for 61% of the total indigenous RHD burden,7 attracting the greatest risk of poor outcomes, especially during pregnancy.
Pregnancy remains a World Health Organisation (WHO) Class IV contraindication in severe MS, due to maternal and foetal morbidity and mortality;5 however, there is a paucity of information regarding the management of severe MS in women of childbearing age or who are pregnant, particularly if they remain asymptomatic. The current guidelines are based on expert consensus which strongly recommends pregnancy avoidance or consideration of pregnancy termination, and do not address or acknowledge cultural sensitivities, varying levels of medical literacy or socioeconomic constraints of patient populations where RHD is likely more prevalent. Management of an already pregnant patient focuses on a combination of pharmacological agents including beta-blockers and diuretics, and clinical monitoring to identify the development of intervention indications.5,8 Percutaneous valvular intervention is recommended preconception. The intrapartum intervention has been reported but only in persistently symptomatic patients between second and third trimesters9 to consider organogenesis of the foetus. This does not take into account the hyperactive mammary tissue exposed to radiation, or the longer-term risk of childhood malignancy. Current guidelines do not account for many of these issues, or the timing and utility of serial echocardiographic assessments to guide percutaneous intervention as pregnancy develops.
This case demonstrates a number of important points. Achievement of pregnancy avoidance may not always be achieved despite its prescription. Serial echocardiography in combination with stress testing and physiological assessment for the surveillance of MV gradients, symptoms, and overall function during pregnancy may be utilized in asymptomatic patients to guide optimization of medical therapy, as well as the timing of percutaneous BMV. We have also demonstrated the safe and successful deferral of percutaneous BMV until post-partum in asymptomatic patients, protecting both the developing foetus and also maternal mammary tissue which remains increasingly active postpartum from potentially harmful radiation.
Our case highlights the importance of patient-specific care and that further understanding of severe MS management in women of childbearing age and intrapartum is required to improve maternal and foetal outcomes.
Lead author biography
Joanne M. H. Eng-Frost is a Cardiology Advanced Trainee at Flinders Medical Centre in Adelaide, Australia. She completed a Bachelor of Science (Biomedical Science) degree with Honours in Physiology at the University of Adelaide, Australia before earning a Doctor of Medicine (MD) degree at Flinders University, Australia. Her clinical interests include structural heart disease and interventional cardiology.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab010_Supplementary_Data Click here for additional data file. | MATERNAL DOSE AT EXPOSURE: 25 MG, BID | DrugDosageText | CC BY-NC | 33693306 | 20,151,132 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Spinal fracture'. | Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center.
Cancer and osteoporosis have high incidence rates in older populations. However, the treatment of osteoporosis among cancer patients has not been adequately described. Our purpose was to clarify the current practice patterns of osteoporosis treatment among cancer patients in an academic cancer center, and to analyze the efficacy of treatment interventions. Patient records from April 2009 to March 2018 were retrospectively reviewed, and the study included a total of 316 cancer patients with osteoporosis. After patients' data extraction, the patients were divided into two groups, with (n = 144) or without treatment (n = 172), and compared the outcomes of these groups to evaluate the medication effect. The primary outcome was new radiographic fragility fractures during the study period. The related factors associated with fracture injuries and the rate of adverse events, such as osteonecrosis in the jaw and atypical femoral fractures, were analyzed. The rate of treatment intervention was 45.6% among the patient groups. Among patients in the study group, breast cancer patients (n = 107) were mostly treated (n = 79, 73.8%) with oral bisphosphonate. A significant difference in new fracture rate was observed between the two groups (treatment group, 30.6%; non-treatment group, 54.7%), and the risk of fracture was 42% lower in the treatment group (hazard ratio, 0.58; 95% confidence interval, 0.39-0.86; p<0.05). Previous chemotherapy, steroid use, and older age were significantly associated with increased rate of new fragility fractures. The adverse event rate was 3.5% (presented in five cases). Older cancer patients who receive chemotherapy or steroids are strongly recommended undergo bone quality assessment and appropriate osteoporosis treatment to improve their prognosis.
Introduction
Treatment of osteoporosis is essential for maintaining a good quality of life in older individuals [1, 2]. Despite preventative efforts, bone fragility increases with age. Therefore, even older people in good health are required to make a steady effort to avoid problems caused by bone fragility, which can often be challenging [3, 4]. Additionally, cancer is a well-known disease that occurs in older populations. However, the treatment of osteoporosis among cancer patients has not been adequately described, despite the huge risk of developing osteoporosis. The International Society of Geriatric Oncology (ISGO) group reported that classical factors including age, sex, family history of hip fractures, comorbidities, as well as corticosteroid, tobacco, and alcohol consumption are emerging as prevalent risk factors for osteoporosis in cancer patients [5]. Moreover, another study reported that the severity of bone disease and number of lesions help identify patients who are at risk of bone failures, including fragility fractures [6]. However, few studies have examined the incidence of adverse events associated with osteoporosis in cancer patients with such risk factors.
The ISGO group also reported that even the treatment recommendations are merely a summary of current knowledge and need further discussion because of the lack of study data. Osteoporosis is often misunderstood as a disease that is not fatal, as there are no symptoms in many cases. However, a decrease in the activity levels or immobilization caused by osteoporotic fragility fractures could be a major obstacle associated with cancer chemotherapies and is directly related to the worsening of cancer outcomes [7–10]. Therefore, it is important to prevent osteoporotic fractures in cancer patients. However, few studies have examined the effects of treatment interventions for osteoporosis in cancer patients. Although there is a growing interest in particular fields to preserve bone health, such as bone fragility associated with hormone treatment [3, 11], a comprehensive analysis of the treatment intervention rate for osteoporosis among cancer patients has not been conducted.
This study aimed to provide an overview of osteoporosis treatment efforts implemented by our center hospital institution for cancer treatment and to identify the effect of preventative medication on new fragility fractures. We expected to observe a higher intervention rate of osteoporosis treatment in patients who received hormone therapy, such as breast or prostate cancer patients. We also hypothesized that the therapeutic intervention would be effective in preventing new fragility fractures, as observed in previous studies [12, 13], and if a similar therapeutic effect is observed in cancer patients, then treating osteoporosis may also improve cancer treatment outcomes.
Materials and methods
Study design and participants
This retrospective study was approved by Aichi Cancer Center institutional ethics committee (approval number 364). After approval, data from our center’s medical records from April 2009 to March 2018 were obtained. As this was a retrospective cohort study, the need for informed consent was waived by our ethics committee, but all participants were given the option to decline participation by way of opting out through the website.
Following the Japanese osteoporosis prevention and treatment guidelines of 2015, the inclusion criteria included a history of vertebral or femoral fragility fractures or a dual energy X-ray absorptiometry (DXA)-scanned young adult mean score <70%. This criteria extracted all cancer patients aged >40 years who could be newly diagnosed with osteoporosis in our hospital. The exclusion criteria were history of diagnosis or treatment of osteoporosis before participation, pathological fractures with bone metastasis, age <40 years [14, 15], and follow-up period <6 months.
After extracting data from 316 patients who met the criteria, we investigated the patient demographics, cancer type, cancer treatment, and whether osteoporosis was treated or not. The primary outcome was new radiographic fragility fractures during the study period. To detect fragility fractures, data were reviewed from all imaging studies, including conventional lateral spine radiographic photos, computer tomography scans, and spinal magnetic resonance imaging, that were conducted during the follow-up period in each patient. For these techniques, evaluation was performed by two independent orthopedic surgeons, and if the evaluation differed between surgeons, senior orthopedic surgeons judged the results. The average frequency of evaluation in each department was 2–3 months. Treatment intervention of osteoporosis was defined as treatment with anti-osteoporotic agents >6-month period, and steroid use was defined when a patient received prednisolone 7.5 mg/day for more than 3 months [16].
Data analysis
We grouped patients based on whether they received treatment or not. The data of patients treated with oral bisphosphonates (treatment group, n = 101) were compared with the data of those without treatment (non-treatment group, n = 172) to determine the medication effects for preventing new radiographic fragility fractures. The cumulative fracture rate was described using a Kaplan–Meier curve, and a log-rank test was performed to compare the intergroup differences. Additionally, a Cox proportional hazard regression model was applied to evaluate the risk factors associated with new fracture injuries. The factors examined were sex, age, method of diagnosis, cancer type, presence of bone metastases or duplicate cancers, history of chemo/radiotherapy, steroid use, and treatment intervention. Then, a multivariate analysis was conducted with all variables from the univariate analysis. All analyses were performed using STATA/SE version 14.2 (StataCorp, College Station, TX, USA), and the level of significance was set at p<0.05.
Results
In total, 316 cancer patients (mean age, 70.0 [range 40–93] years; sex, 81 men [25.6%] and 235 women [74.4%]) were diagnosed with osteoporosis during the 10-year study period. The patient demographics are presented in Table 1. Of these, 48 (15.2%) and 29 patients (9.2%) had bone metastasis and double cancers, respectively. Moreover, 188 (59.5%) and 79 patients (25.0%) had previously undergone chemotherapy and radiotherapy, respectively. In relation to chemotherapy, steroid injections were used in 46.8% (n = 148) of patients. The mean follow-up period was 34.2 (range, 6.1 to 114.5) months, and the total number of deaths during the study period was 96 (30.4%).
10.1371/journal.pone.0248188.t001 Table 1 Patient demographics.
Characteristics Total (n = 316) Treatment (n = 144) Non-treatment (n = 172) p-value
Age, years
Mean (range) 70.0 (40–93) 67.4 (50–86) 71.4 (51–84) 0.06
Sex, female 74.4% (235) 88.9% (128) 62.2% (107) <0.01
Diagnosis
*DXA 32.9% (104) 56.3% (81) 13.4% (23)
Vertebral fracture 60.1% (190) 38.2% (55) 78.5% (135)
Femoral fracture 7.0% (22) 5.6% (8) 8.1% (14)
<0.01
Cancer
Breast 34.0% (107) 54.9% (79) 16.3% (28)
Gastrointestinal 22.8% (72) 13.9% (20) 30.2% (52)
Lung 14.9% (47) 9.7% (14) 19.2% (33)
Blood 13.3% (42) 12.5% (18) 14.0% (24)
Head and neck 7.9% (25) 2.7% (4) 12.2% (21)
Others 7.3% (23) 6.3% (9) 8.1% (14)
<0.01
Double cancer 9.2% (29) 5.8% (10) 11.0% (19) 0.21
Bone metastasis 15.2% (48) 19.4% (28) 11.6% (20) 0.05
Previous radiotherapy 25% (79) 19.4% (28) 29.7% (51) 0.04
Previous chemotherapy 59.5% (188) 56.2% (81) 62.2% (107) 0.28
Steroid use 46.8% (148) 47.2% (68) 46.5% (80) 0.9
Adverse effect <0.01
Additional fracture 43.7% (138) 30.6% (44) 54.7% (94)
Jawbone necrosis 2.1% (3) 0% (0)
Atypical femoral fracture 1.4% (2) 0% (0)
*DXA: dual energy X-ray absorptiometry.
Patients were mostly diagnosed with breast cancer (n = 107, 34.0%), followed by gastrointestinal (n = 72, 22.8%), lung (n = 47, 14.9%), and blood cancer (n = 42, 13.3%). Contrary to our expectation, prostate cancer patients were almost undiagnosed (<2%). The total rate of medications was 45.6% (n = 144), with 70.1% (n = 101) of patients receiving oral bisphosphonate, followed by 9.7% (n = 14) of receiving zoledronic acid injections. An active vitamin D3 form, the one most commonly prescribed in general practice, was used in 9% of all cases. Denosumab was used in 6.9% of the treatment-group participants. Apart from the healthy population, only one participant (0.7%) received a teriparatide injection at another clinic (Fig 1). Osteoporosis was most frequently treated in breast cancer patients (n = 79, 73.8%), followed by blood (n = 18, 42.9%), lung (n = 14, 29.8%), and gastrointestinal cancer patients (n = 20, 27.8%). However, only 16.0% of head and neck cancer patients received medication for osteoporosis (Fig 2).
10.1371/journal.pone.0248188.g001 Fig 1 Key drugs used for osteoporosis treatment and frequency of anti-osteoporotic agents.
Of the oral bisphosphonates, 54.9% were alendronate and the rest were risedronate. The active form of vitamin D3 included eldecalcitol and alfacalcidol.
10.1371/journal.pone.0248188.g002 Fig 2 Treatment intervention rate.
The total rate of treatment intervention was 45.6%, and if breast cancer patients were excluded, it reduced to 31.0%. Approximately 73.8% of breast cancer patients were treated. In contrast, only 16.0% of head and neck cancer patients were treated.
The total rate of new fragility fractures during the study period was 43.7% (n = 138) (i.e., 30.6% [n = 44] and 54.7% [n = 94] in the treatment and non-treatment groups, respectively). Although there was clearly a statistically significant difference, only the statistics of the oral bisphosphonate group (n = 101) were examined because of the need for uniformity in the treatment agents. The Nelson-Aalen cumulative hazard estimate showed a great difference in the risk of new radiological fragility fractures between the treatment (n = 101) and non-treatment groups (n = 172), and the log-rank test demonstrated a significant difference among these groups (p<0.001) (Fig 3). However, the greater percentage of DXA-diagnosed patients could be a bias for the treatment group. We also performed the analysis after excluding the DXA-diagnosed patients, but it presented similar results (Fig 4). Although the difference between the two groups was small, the log-rank test also showed a significant difference between the two groups (p<0.05).
10.1371/journal.pone.0248188.g003 Fig 3 Cumulative risk of fracture (treatment vs non-treatment group).
The Nelson-Aalen cumulative hazard estimate showing the difference in the risk of additional fragility fractures between the two groups. The log-rank test showed a significant difference between these two groups (p<0.001).
10.1371/journal.pone.0248188.g004 Fig 4 Cumulative risk of fracture without DXA-diagnosed patients (treatment vs non-treatment group).
When patients diagnosed by DXA were excluded, the difference between the two groups narrowed. However, the log-rank test still showed a significant difference between these groups (p = 0.047). DXA, dual energy X-ray absorptiometry.
The multivariate analysis revealed that previous chemotherapy (hazard ratio [HR], 1.78; p = 0.019; 95% confidence interval [CI], 1.10–2.89), steroid use (HR, 1.68; p = 0.018; 95% CI, 1.09–2.58), and older age (HR, 1.03; p = 0.007; 95% CI, 1.01–1.05) were positively related to the increase in the rate of getting another fracture. Treatment intervention (HR, 0.58; p = 0.007; 95% CI, 0.39–0.86) and DXA diagnosis (HR, 0.29; p<0.001; 95% CI, 0.15–0.51) showed an inverse result (Table 2).
10.1371/journal.pone.0248188.t002 Table 2 Factors related to the risk of new radiological fragility fractures.
Factors Hazard ratio p-value 95% CI
Previous chemotherapy 1.78 0.019 1.10–2.89
Steroid use 1.68 0.018 1.09–2.58
Older age 1.03 0.007 1.01–1.05
Diagnosed with DXA 0.29 <0.001 0.15–0.51
Treatment intervention 0.58 0.007 0.39–0.86
CI: confidence interval; DXA: dual energy X-ray absorptiometry.
The most prevalent new radiological fragility fractures were vertebral (76.8%, n = 106) and femoral fractures (11.6%, n = 16). An adverse effect from using anti-osteoporotic drugs was observed in five cases (3.5%). This included two cases (1.4%) of atypical femoral fractures with long-term use of zoledronic acid, and three cases (2.1%) of jawbone necrosis in relation to the use of zoledronic acid or denosumab injections. Patients with fractures underwent open reduction and internal fixation at our department without any complications. Jawbone necrosis patients were treated at the dental department of our hospital, and all patients recovered during the follow-up period.
Discussion
Although the prognosis of cancer patients has improved, it is necessary to treat osteoporosis to maintain the performance status (PS) for chemotherapies [5, 17]. With this perspective, we found that medication had a significant influence on osteoporosis even in cancer patients. The use of anti-osteoporotic agents could reduce the risk of new radiological fragility fractures by 42%. However, the treatment rate itself was below 50%, despite the existence of the national guidelines. These results were fairly better than those of the general population (i.e., approximately 20% in Japan) [18, 19].
Disparities in treatment interventions between departments were large, with well-conducted interventions in breast and hematology departments, but not in lung, gastrointestinal, or head and neck surgery departments. This may stem from the differences in the cancer treatment itself, although we have not studied the exact reasons for this issue. For example, breast cancer treatment is directly related to bone metabolism with the use of hormone treatment, such as tamoxifen or aromatase inhibitors. There are several guidelines that have already been published for bone-directed treatment, and Hadji et al. [11] have updated the treatment algorithm for better assessment of fracture risk. In addition, Colzani et al. [20] reported an increased risk of fragility fracture in patients using aromatase inhibitors compared with patients using tamoxifen (HR, 1.48; 95% CI, 0.98–2.22). Therefore, in such cases, a treatment intervention should be provided. In these cases, physicians and patients may easily accept osteoporosis treatment because it is already included in the cancer treatment.
Concerning risk factors, chemotherapy and associated steroid use had an obvious effect on the development of new radiological fragility fractures. Although chemotherapy itself is a risk factor for osteoporosis, a certain amount of steroid is often used as an antiemetic in chemotherapy, and this may worsen the patient’s comorbidities, which were not considered fatal. Many cancer patients are prescribed more steroids than the diagnosis criteria of steroid-induced osteoporosis [16], and the risk of developing this condition is dose dependent [21, 22]. In this study, patients who received chemotherapy and used steroids were at an increased risk of developing additional fractures, indicating that more careful interventions are needed for these patient groups.
After considering these results, we propose some suggestions for individual physicians who are engaged in cancer treatments. First, as the use of osteoporotic drugs has an evident effect on preventing new fragility fractures, physicians should take osteoporosis seriously to provide an efficient cancer treatment. Indeed, the treatment of osteoporosis is a time-consuming process, as oral bisphosphonates are sometimes not fully effective in patients who have difficulty with oral intake or are unable to receive oral medication. However, in recent years, several new anti-osteoporotic agents, such as annual zoledronic acid, semi-annual denosumab, or newly developed romosozumab injections have been released and are gradually being used. These new drugs are potentially therapeutically beneficial and cost effective for cancer patients who must undergo multiple medical treatments [23–25]. The use of appropriate drugs for osteoporosis may also reduce the use of unnecessary analgesics, such as opioids or morphine, which can ultimately lead to a worsened PS. Second, as aforementioned, an increased rate of anti-osteoporotic agent usage can be attained as long as it can be linked to the cancer treatment itself. For example, when the diagnostic criteria for steroid osteoporosis are correctly applied to all cancer patients receiving chemotherapy, osteoporosis treatment could be included in their cancer treatment and physicians may prevent the decrease of the PS by avoiding fragility fractures caused by osteoporosis. Finally, there is an urgent need to correct disparities among medical departments. Common criteria are needed for initiating osteoporosis treatment in an institution. Moreover, establishing a cancer board that includes all departments may also help improve the rate of treatment interventions.
Regarding the adverse effects of using anti-osteoporotic drugs, jawbone necrosis and atypical femoral fracture were observed in 1.4%, and 2.1% of patients, respectively. This was similar to those previously reported by Edwards et al. [26] and Lipton et al. [27]. Our institution routinely requires dental consultations for screening oral conditions before starting anti-osteoporotic agent administration, and patients who were diagnosed with a high risk of jawbone necrosis underwent dental treatment before using these agents [28]. In addition, there were three cases of atypical femoral fractures in our study group, and all were treated surgically at our orthopedic department without any complications.
In this study, we had few patients who used teriparatide, which is rarely used for osteoporosis treatment in recent years. After Subbiah et al. [29] reported the risk of teriparatide-induced osteosarcoma, the use of teriparatide is avoided for cancer patients. However, recent research has provided new evidence concerning the use of teriparatide [25, 30, 31]. Interestingly, Gilsenan et al. reported that the incidence of osteosarcoma associated with teriparatide use during a 15-year period was not different than what was expected based on the background incidence rate of osteosarcoma after examining data from a US database [30]. Besides, other new agents, such as romosozumab, humanized IgG2 monoclonal antibody, or annual zoledronic acid, were allowed to be used for the treatment of cancer patients. These relatively new drugs will be used more aggressively for such patients in the future.
However, this study had several limitations. First, there were differences between the two groups. Although we conducted the analysis without factors that could affect the results, the potential difference may have affected the study results. Additionally, we had no detailed data on cancers and chemo/radiotherapies, and these unknown factors may also have affected the results. Second, we applied Japanese national guidelines for the prevention and diagnosis of osteoporosis, which are slightly different from the World Health Organization guidelines. This may have affected treatment interventions in particular for patients from different departments, such as the breast oncology department. Third, we defined treatment interventions as those provided for more than 6 months, as cancer patients often have poor prognoses. However, most related studies set this intervention period as over 1 year; therefore, some may doubt the effect of treatment interventions.
Despite these limitations, the current study provided a sound analysis of the effect of osteoporosis treatment among cancer patients in our tertiary center. We found that the medication effect was quite substantial, while the incidence of adverse events was low. Therefore, older cancer patients who receive chemotherapy or use steroids are strongly recommended to use anti-osteoporotic drugs to maintain their PS. However, there is still a need to study the effect of osteoporotic treatment in terms of specific cancer types or agents, as related research is lacking. From these viewpoints, further research is required to improve the quality-of-life associated with cancer treatment of patients to achieve better prognoses.
Supporting information
S1 Data (XLSX)
Click here for additional data file.
S1 Checklist (DOCX)
Click here for additional data file.
The authors thank Hidemi Ito and Kenichi Yoshimura for their statistical support.
10.1371/journal.pone.0248188.r001
Decision Letter 0
Blank Robert Daniel Academic Editor
© 2021 Robert Daniel Blank
2021
Robert Daniel Blank
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version0
2 Nov 2020
PONE-D-20-33343
Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center
PLOS ONE
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There are several important issues that you must address before I send this MS to other reviewers.
1. Please check your MS against STROBE standards for cohort studies and add the STROBE checklist to your MS.
2. Please show p-values for table 1. My inspection of the table suggests that the treated/untreated groups differ. This should be checked explicitly, as it is an important potential source of confounding in your subsequent analysis.
3. Date of entry into study should be explicitly defined, and survival curves plotted based on study entry, not diagnosis of osteoporosis. It is necessary to unpack those who were already being treated prior to cancer diagnosis.
4. What about osteoporosis based on other low trauma fractures beside vertebral or femoral?
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10.1371/journal.pone.0248188.r002
Author response to Decision Letter 0
Submission Version1
8 Dec 2020
November, 30, 2020
Dear Editor:
Thank you for checking the manuscript. We have summarized the corrections below based on your review. Thank you in advance for your kind help.
Best regards,
Nasa Fujihara
Additional Editor Comments:
1. Please check your MS against STROBE standards for cohort studies and add the STROBE checklist to your MS.
⇒ The checklist is attached at the end of the manuscript.
2. Please show p-values for table 1. My inspection of the table suggests that the treated/untreated groups differ. This should be checked explicitly, as it is an important potential source of confounding in your subsequent analysis.
⇒ We have included it because it affects the results of the analysis as you pointed out. Although there were fewer women in the untreated group, which may lead to a lower risk of fracture, the results actually showed a higher risk of fracture.
3. Date of entry into study should be explicitly defined, and survival curves plotted based on study entry, not diagnosis of osteoporosis. It is necessary to unpack those who were already being treated prior to cancer diagnosis.
⇒As you pointed out, the starting point was the time of participation in the study, and we have corrected this to include the notation in the graph.
Also, patients with a diagnosis of osteoporosis prior to the start of the study were excluded and this has been noted.
4. What about osteoporosis based on other low trauma fractures beside vertebral or femoral?
⇒ To clarify the definition, we only included the cases with vertebral or low-energy femoral fractures, or less than 70% of YAM value according to the Japanese diagnostic criteria of osteoporosis. So as you pointed out, the other low trauma fracture with high YAM value cases are not included. However, results includes all fragility fractures caused from low energy trauma.
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10.1371/journal.pone.0248188.r003
Decision Letter 1
Blank Robert Daniel Academic Editor
© 2021 Robert Daniel Blank
2021
Robert Daniel Blank
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version1
23 Dec 2020
PONE-D-20-33343R1
Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center
PLOS ONE
Dear Dr. Fujihara,
Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.
Reviewer 1 wishes a few additional details regarding drug treatment. Reviewer 2 wishes a higher standard of English syntax and usage. Editor agrees with both reviewers.
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Academic Editor
PLOS ONE
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Reviewer #1: The result is somehow expected where those being treated should have a lower incidence of fragility fracture. It is supported by this piece of research. 9% of the patients were being treated with Vitamin D. Many current studies showed the important role of Vitamin D in patients with cancer especially breast cancer. Is Vitamin D considered a treatment for osteoporosis in patient with cancer in your centre? What kind of Vitamin D was being used? Was it single therapy or in combination with anti-osteoporosis medicines? Did you look at the vitamin D level of your patients, both baseline and after treatment?
Although it was mentioned in your document that there might be a role of teriparatide in treating cancer patients with osteoporosis, it is clearly stated in the teriparatide product information that it should not be used in cancer patients with skeletal metastatic lesion. What is your view on this?
Reviewer #2: The paper is scientifically sound and presents useful information. However, the written language used in the manuscript is not appropriate for a scientific publication (For example: first person used not be in scientific manuscript.
Editing of the paper by an individual scientist with English as their language would aid in acceptance of the paper.
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10.1371/journal.pone.0248188.r004
Author response to Decision Letter 1
Submission Version2
3 Feb 2021
February 3, 2021
Dear Dr. Blank,
Academic Editor
PLOS ONE
Dear Editor:
We would like to thank you for your response and for giving us the opportunity to improve and resubmit our manuscript (PONE-D-20-33343R1) entitled "Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center." We are hereby resubmitting a revised manuscript conforming to all of the reviewers’ comments. In particular, we have addressed all the reviewers’ comments in a point-by-point manner and revisions are indicated in red font in the revised manuscript. We hope that the revised manuscript is now suitable for publication in your journal.
Thank you for your consideration. I look forward to hearing from you.
Sincerely,
Nasa Fujihara,
Section of Orthopedic Surgery, Aichi Cancer Center
1-1 Kanokoden Tikusa-ku,
Nagoya City, Aichi, Japan 464-8681
Email: nfujihara@aichi-cc.jp
Phone: 052-762-6111
FAX: 052-762-6111
Reviewer #1: The result is somehow expected where those being treated should have a lower incidence of fragility fracture. It is supported by this piece of research. 9% of the patients were being treated with Vitamin D. Many current studies showed the important role of Vitamin D in patients with cancer especially breast cancer. Is Vitamin D considered a treatment for osteoporosis in patient with cancer in your centre? What kind of Vitamin D was being used? Was it single therapy or in combination with anti-osteoporosis medicines? Did you look at the vitamin D level of your patients, both baseline and after treatment?
Although it was mentioned in your document that there might be a role of teriparatide in treating cancer patients with osteoporosis, it is clearly stated in the teriparatide product information that it should not be used in cancer patients with skeletal metastatic lesion. What is your view on this?
Response
We would like to thank the reviewer for evaluating our manuscript and for these constructive comments.
First, regarding vitamin D, we did use not the natural form of vitamin D that is often discussed nowadays. “Vitamin D” described in this study was actually “eldecalcitol” or “alfacalcidol,” which is an active vitamin D3 prodrug. Besides, we do not have a specific hospital or medical department protocol for applying Vitamin D drugs. Probably, the use of Vitamin D has been reported in some cases of breast cancer, as the reviewer stated.
However, in Japan, “eldecalcitol” or “alfacalcidol” is often prescribed as an initial drug for osteoporosis treatment. Please note that we have edited the text and figures to make it clear that we used an active vitamin D3 prodrug. Especially, we have added the following sentences in the revised manuscript:
“An active vitamin D3 form, the one most commonly prescribed in general practice, was used in 9% of all cases.” (Lines 137–138)
“The active form of vitamin D3 included eldecalcitol and alfacalcidol.” (Line 147)
Moreover, teriparatide's contraindication for cancer patients with skeletal metastatic lesion is mainly based on past studies showing that teriparatide increased osteosarcoma in rats. However, in this study on rats, the used doses were dozens of times higher and provided for a longer period of time than those given to humans. Therefore, there are many arguments regarding whether it can directly apply to humans. In fact, as a recent study that analyzed the data of patients from a US database did not show any evidence concerning the role of teriparatide in increasing osteosarcoma or malignant bone tumors, we believe that the indications for teriparatide will be expanded in the future. Alternatively, another new osteoporosis drug, romosozumab, is indicated for cancer patients and may be a useful treatment option. Please note that we have included these issues in the discussion of the revised manuscript as follows: “However, recent research has provided new evidence concerning the use of teriparatide (25, 30, 31). Interestingly, Gilsenan et al. reported that the incidence of osteosarcoma associated with teriparatide use during a 15-year period was not different than what was expected based on the background incidence rate of osteosarcoma after examining data from a US database (30). Besides, other new agents, such as romosozumab, humanized IgG2 monoclonal antibody, or annual zoledronic acid, were allowed to be used for the treatment of cancer patients. These relatively new drugs will be used more aggressively for such patients in the future.”
(Lines 256–263)
Reviewer #2: The paper is scientifically sound and presents useful information. However, the written language used in the manuscript is not appropriate for a scientific publication (For example: first person used not be in scientific manuscript.
Response
We would like to thank the reviewer for evaluating our manuscript and for this comment. Please note that we have sent our manuscript to an English editing company (Editage) for English proofreading. We hope that the level of English has significantly improved in the revised manuscript.
Attachment Submitted filename: Responce_to_Reviewers_0203.docx
Click here for additional data file.
10.1371/journal.pone.0248188.r005
Decision Letter 2
Blank Robert Daniel Academic Editor
© 2021 Robert Daniel Blank
2021
Robert Daniel Blank
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version2
22 Feb 2021
Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center
PONE-D-20-33343R2
Dear Dr. Fujihara,
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10.1371/journal.pone.0248188.r006
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PONE-D-20-33343R2
Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center
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PLOS ONE | DENOSUMAB | DrugsGivenReaction | CC BY | 33705450 | 20,100,542 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Osteosarcoma'. | Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation.
Giant cell tumor of bone (GCTB) is a locally aggressive lesion of intermediate malignancy. Malignant transformation of GCTB is a rare event. In 2013, the humanized monoclonal antibody against receptor activator of nuclear factor-κb-Ligand (RANKL) denosumab was approved for treatment of advanced GCTB. Since then, several reports have questioned the role of denosumab during occasional malignant transformation of GCTB. We report on three patients with H3F3A-mutated GCTBs, treated with denosumab. The tissue samples were analysed by histomorphology, immunohistochemistry, and in two instances by next generation panel sequencing of samples before and after treatment. One patient had a mutation of ARID2 in the recurrence of the GCTB under treatment with denosumab. One patient developed a pleomorphic sarcoma and one an osteoblastic osteosarcoma during treatment. Sequencing revealed a persisting H3F3A mutation in the osteosarcoma while the pleomorphic sarcoma lost the H3F3A mutation; however, a FGFR1 mutation, both in the recurrence and in the pleomorphic sarcoma persisted. In addition, the pleomorphic sarcoma showed an AKT2 and a NRAS mutation. These data are inconclusive concerning the role denosumab plays in the event of malignant progression/transformation of GCTB and point to diverging pathways of tumor progression of GCTB associated with this treatment.
Introduction
Giant cell tumor of bone (GCTB) was first described by Jaffe et al.1 in 1940 and makes up about five percent of all primary bone lesions2,3; GCTB is typically located in the epiphyseal region of the long tubular bones such as the distal femur and the proximal tibia3,4. Based on the WHO-Classification for tumors of soft tissue and bone, GCTB is considered to be an aggressive and rarely metastasizing tumor and therefore is regarded as tumor of intermediate malignancy (ICD-O: 9250/1)5. Metastatic lesions most commonly occur in the lungs4,6. In rare cases, a high-grade malignant neoplasia is identified arising in GCTB (primary malignancy in GCTB or after previous radiotherapy (in both instances classified as ICD-O: 9250/3)).
Histologically, the GCTB mainly consists of three different cell types. These are the neoplastic spindle-shaped stromal cells that show enhanced synthesis of receptor activator of nuclear factor-κb ligand (RANKL) and the large multinucleated osteoclast-like giant cells and their monocytic precursors expressing the corresponding receptor, i.e., receptor activator of nuclear factor-κb (RANK)7,8. The stroma cells are the neoplastic component of GCTB and harbour a characteristic point mutation at the histone gene H3F3A leading to a substitution of glycine by tryptophan at position 34 (G34W). The increased synthesis of the RANKL by the neoplastic cells leads to enhanced bone resorption by the osteoclast-like giant cells through the RANK/RANKL signalling pathway, which in turn are responsible for the locally aggressive growth.
Intralesional curettage is the primary treatment option for GCTB6. The rate of local recurrence after intralesional curettage ranges from 30 to 40%3,9. Denosumab was first approved for the treatment of osteoporosis under the brand name PROLIA in 2010 and was later approved for the treatment of GCTB in 2013 under the brand name XGEVA. Denosumab is a humanized monoclonal IgG2-anti-RANK-Ligand-antibody. This monoclonal antibody binds to RANKL and inhibits the interaction between the spindle-like stromal cells and the osteoclast-like giant cells, and thereby prevents local bone resorption, thus mimicking the effect of osteoprotegerin, a physiological RANKL-antagonist6,7.
Clinical case presentation
Patient one is a female, first diagnosed with GCTB in 2015 at the age of 33. The tumor measured 12 cm and was located in the pelvis; she was treated by a complete (R0) resection. In 08/2016 a denosumab treatment was started (120 mg subcutaneously every 4th week) until 06/2017 due to recurrence in the pelvis confirmed by a biopsy. The patient is well and shows no further signs of progression.
Patient two is a male that was diagnosed with a tumor of the sacrum measuring 13 cm in 03/2014 at the age of 20. A biopsy was performed and the diagnosis of GCTB was confirmed by detection of the H3F3A G34W mutation. In 04/2014 an incomplete resection of the tumor with instillation of alcohol 90% was performed. A fistula, which developed shortly after the first surgery, was resected.
In 12/2014, nine months after resection of the GCTB, a recurrence was diagnosed and denosumab treatment was started with 120 mg every 4 weeks until 05/2016. In 2017 the patient underwent palliative surgery. A CT-Scan showed a large local recurrence and pulmonary as well as liver lesions highly suspicious of metastases. The tumor mass was resected in 07/2017 and a high-grade osteosarcoma with angioinvasion harbouring the H3F3A G34W mutation was diagnosed.
The patient died in 08/2017 due to tumor progression and sepsis.
Patient three, a woman, is a follow-up initially published by Aponte-Tinao et al.10 in 2015. These authors reported the case of a 20-year-old female who was first diagnosed with GCTB in 2009. The GCTB was located at the right proximal tibia and was treated by intralesional curettage. She was diagnosed with a recurrence of GCTB about one year later in 2010 and was treated by en-bloc resection. The following two years were uneventful until a follow-up CT-scan showed a second recurrence in 2013 and denosumab therapy was started. The first application was a subcutaneous dose of 360 mg followed by 120 mg subcutaneously every 4 weeks. About one year after beginning of treatment with denosumab, the patient noticed a palpable, painful mass in the popliteal fossa. A CT-Scan showed that the mass included two sections of different density. An open biopsy was performed and histologic workup showed a high-grade undifferentiated pleomorphic sarcoma besides the GCTB. Subsequently an above-knee amputation was performed. Several tissue blocks were available for further histological analysis of the resection specimen. The patient is well and shows no signs of progression.
Methods
The samples were analysed by conventional histology using haematoxylin–eosin (HE) staining of sections of paraffin-embedded tissue. Immunohistochemistry was performed as described using a mutation specific monoclonal antibody for detection of the H3F3A G34W mutation (Anti H3.3 G34W clone 31-1145-00; RevMab Biosciences, San Francisco, CA, USA; dilution 1:400); for detection of proliferation indices the Ki-67 antibody (M7240, Dako, Glostrup, Denmark; dilution 1:200) was applied11.
The alkaline phosphatase/RED detection system (Dako) was used for immunohistochemistry on formalin-fixed and paraffin-embedded tissue via the avidin–biotin-complex-method. The samples were pseudonymized according to the German law for correct usage of archival tissue for clinical research. The research was approved by the local ethics committee of the University of Ulm (reference 369/17) and was in compliance with the ethical principles of the World Medical Association Declaration of Helsinki. Informed consent was obtained from all patients.
Isolation of tumor DNA from FFPE tissue
For isolation of genomic DNA from the formalin fixed paraffin embedded (FFPE) tissue samples, 5 μm tissue slices were transferred to glass slides. To estimate the area containing the tumor, HE stained FFPE tissue slices (2 µm) were validated by an expert pathologist. The tumor-harbouring areas of the FFPE tissue were subjected to a DNA extraction procedure using the QIAamp DNA FFPE tissue kit (QIAGEN, Hilden, Germany) according to manufacturer’s instruction. DNA purity and concentration were determined fluorometrically (Qubit 2.0; Invitrogen, Carlsbad, CA, USA).
We further performed Sanger-Sequencing for H3F3A G34W for all tissue samples of patient 1 and patient 3. Gene sequencing (Sanger) was performed according to a diagnostic standard protocol. The cell line A498 was used as negative control. The graphs were generated with FinchTV 1.4.0 (Geospiza Inc., Seattle Washington, USA)12.
Next generation sequencing
For molecular characterization of both tumor tissue and ctDNA, we employed a targeted re-sequencing methodology using the GeneRead V2 chemistry (QIAGEN, Hilden, Germany) and a custom-made re-sequencing panel including primers for all exons of a panel of 37 genes (primer sequences and locations of target areas are available upon request). Target enrichment, amplicon processing, and library generation were performed according to the manufacturer’s instructions. For target enrichment, we included 10–40 ng (DNA from FFPE tumor and non-neoplastic tissue). Successful target enrichment and library generation was checked using the High Sensitivity DNA kit on a bioanalyzer device (Agilent, Santa Clara, CA, USA). Libraries were diluted to 10 pM solutions and the sequencing was performed on a MiSeq platform (Illumina, San Diego, CA, USA) using the V2 chemistry. Mean read depth on target region was 2000–8000-fold and 99% of bases were covered at 96–100% on average. The resulting fastq files were subjected to further analysis using the GeneRead web based analysis tool (http://ngsdataanalysis.sabiosciences.com/NGS2/), the Biomedical Workbench software package (QIAGEN, Hilden, Germany), and the Variant Studio software (Illumina, San Diego, CA, USA)13. All identified mutations were manually re-analyzed using the Integrated Genome Viewer Software (Broad Institute, MA, USA).
Single nucleotide polymorphisms (SNP) detected in non-tumor-tissue were excluded from further analysis.
Results
Patient 1
Morphology
Tissue blocks of the primary biopsy, the resection specimen, and the recurrence under denosumab therapy were available. Histological analysis of the biopsy and resection specimen showed a giant cell tumor with typical morphology, consisting of osteoclastic giant cells and a mononuclear spindle cell compartment. The primary tumor showed a strong positivity for the H3.3 G34W detecting antibody in the nuclei of the stromal compartment. Nuclei of osteoclastic giant cells were negative. A second mononuclear cell population was detected being negative for H3.3 G34W which most probably presents osteoclastic precursors. Ki-67 rate was about 5% in the mononuclear cell population. After treatment the tumor revealed a dramatic change in morphology. The number of H3.3 G34W-positive osteoblastic cells was greatly reduced; positive mononuclear cells were still detectable along strands of neoformated osteoid. We detected an intermingled spindle cell compartment negative for H3.3 G34W. The Ki-67 index dropped to less than 1% (Fig. 1). The presence of the H3F3A G34W mutation was further proven by Sanger sequencing.Figure 1 Morphology of Case 1. (A) Typical GCTB with osteoclastic giant cells and intermingled mononuclear cells before therapy (bar = 100 µm). Neoplastic mononuclear cells are positive in a H3F3A G34W staining in the nuclei (B) and about 5% of cells are Ki-67 positive (C). After denosumab therapy GCTB shows induction of neoformated osteoid and complete reduction of giant cells (D), while H3F3A G34W-positive cells are still present (E); insert shows H3F3A-negative spindle cells. Proliferation has dropped to 1% in a Ki67 staining (F).
Panel sequencing of microdissected tissue of the resected tumor and the biopsy of the recurrence revealed a mutation of ARID2 (chromosome 12; position (GRCh37) 46205208, c.292G > A; p.E98K) with an allele frequency of 48% in the tumor recurrence under denosumab treatment. Neither the non-tumorous tissue nor the GCTB before treatment with denosumab harboured this mutation.
Patient 2
Morphology
The biopsy and resection specimen revealed a GCTB with typical morphology of osteoclastic giant cells and mononuclear spindle cells. Ki-67 rate was about 5%. Immunochemistry and sequencing confirmed the diagnosis of GCTB with positive staining for the mutation H3F3A G34W. This diagnosis was verified by Sanger-Sequencing.
Morphology of the resected recurrence revealed a pleomorphic high-grade sarcoma with necrosis and presence of atypical mitotic figures. The sarcoma showed intermingled lace-like neoplastic osteoid and was classified as a high-grade osteosarcoma; an angioinvasion was present. The sarcoma harboured the H3F3A G34W mutation as shown by immunohistochemistry in all tumor cells and a Ki-67 index of 90% (Fig. 2). This presence of the mutation was further confirmed by Sanger sequencing for H3F3A G34W mutation.Figure 2 Morphology of Case 2. Typical morphology of GCTB with osteoclastic giant cells and mononuclear spindle cells (A) neoplastic mononuclear cells with positive H3F3A G34W staining (B) (bar = 100 µm). Staining for Ki-67 shows about 5% positive cells (C). The sarcoma showed presents with polymorphic tumor cells andatypical mitotic figures with necrosis intermingled lace-like neoplastic osteoid intermingled with necrotic bone. An atypical mitotic figure is shown in the insert (D). The sarcoma harboured the H3F3A G34W mutation (E) and had a high rate of Ki-67 (F).
Patient 3
Morphology
The morphology of this tumor has been described in details by Aponte et al.10. In brief, the initial GCTB revealed a typical morphology with osteoclastic giant cells and a mononuclear H3F3A G34W-positive neoplastic tumor population as shown by immunohistological staining and sequencing both of the primary tumor and the recurrence. The Ki-67 index was about 5%. The sarcoma after denosumab treatment showed a high-grade sarcoma (not otherwise specified) with spindle-like to pleomorphic tumor cells and extensive necrosis and a Ki-67 index of 50%.
The sarcoma was negative in an immunohistochemical staining with the monoclonal antibody for detection of H3F3A G34W.
Sequencing of DNA from microdissected tissue of the H3F3A G34W-negative tumor showed a very weak peak for a mutation-specific thymine that was below the detection threshold as shown in Fig. 3.Figure 3 Morphology of Case 3. (1) Biopsy. (2) Resection specimen. (3) Sarcoma. Typical GCTB with osteoclastic giant cells and intermingled mononuclear cells in the biopsy (1A) and the resection specimen (2A) as well as neoplastic mononuclear cells with positive H3F3A G34W staining in the nuclei (1B,2B) (bar = 100 µm). Staining for Ki-67 shows about 1% of positive cells (1C,2C). Sanger-Sequencing for H3F3A G34W shows the mutation specific thymine in tissue of the biopsy (1D) as well as the resection specimen (2D). The sarcoma showed spindle to pleomorphic tumor cells and extensive necrosis (3A) and a high Ki-67 index (3C), however it did not stain positive for H3F3A G34W (3B). Sanger-sequencing of DNA from microdissected tissue of the H3F3A G34W-negative tumor showed a very weak peak for a mutation-specific thymine (3D).
In the panel-sequencing we found a mutation of FGFR1 (chromosome 8; position (GRCh37) 38287303; c354G > A; p.E118) in the resection specimen of the GCTB and in the sarcoma with an allele frequency of 10%, which was not found in the biopsy. We found two additional mutations in the sarcoma tissue for AKT2 (chromosome 19; position (GRCh37) 40742052) and NRAS (chromosome 1; position (GRCh37) 115256669) with a frequency of 26% and 48%, respectively; these two mutations were not present in the initial biopsy or in the resection specimen (Fig. 4) and present intronic mutations with no effect on the protein structure. Supplementary Figs. 1 and 2 summarize the clinical and molecular findings.Figure 4 Summary of SNPs found in the different tissue samples (Case 3). SNPs in the resection: FGFR1 (chromosome 8; position (GRCh37) 38287303; c354G > A; p.E118). SNPs in the pleomorphic sarcoma: FGFR1 (chromosome 8; position (GRCh37) 38287303; c354G > A; p.E118); AKT2 (chromosome 19; position (GRCh37) 40742052); NRAS (chromosome 1; position (GRCh37) 115256669).
Discussion
GCTB is characterized by an enhanced paraneoplastic secretion of RANKL, leading to a shift of normal bone homeostasis to enforced bone resorption due to an increased number of induced non-neoplastic osteoclasts3,14. Denosumab was first approved for treatment of GCTB in 2013 in advanced stage and is a humanized monoclonal IgG2 antibody. Through specific binding to RANKL denosumab blocks the RANK/RANKL signalling. This treatment leads to striking changes in morphology of GCTB characterized by reduction of both, the neoplastic cell compartment and the osteoclasts14. Due to blockage of the RANK/RANKL axis enhanced osteoid neoformation of bone is observed by H3F3A-non-mutated osteoblasts and fibroblastoid spindle cells11.. Mak et al. showed that denosumab reduced the number of osteoclasts and RANKL secretion in vitro, however the neoplastic stromal cells continued to grow after reduction of denosumab, even though at a slower proliferation rate15. The authors conclude that after denosumab treatment the H3F3A-mutated tumor cell pool may reside in the tissue and be reactivated during recurrence15. Besides the role of the RANK axis in the control of bone remodelling and as a crucial factor in GCTB growth, RANKL has an important role for the differentiation of B and T cells as well as for the survival of dendritic cells16,17; by this mechanism, enhanced RANKL synthesis in GCTB may lead to immunosuppression and therefore promote neoplastic transformation18.
On the other hand, nuclear factor κb upregulation by enhanced RANK signalling is discussed to interfere with regulation of oncogenes18. It has been shown that RANKL upregulates the expression of semaphorin 3A20, and may thereby affect growth of cartilage and bone21. Furthermore, in a comparative proteome study of GCTB before and after denosumab therapy several differentially expressed proteins were identified including metalloproteinase 9 being downregulated after denosumab treatment19. Interestingly, we noted a reduction of proliferation of the GCTB after treatment in the recurrences of patient one, however we further detected a H3F3A-negative mononuclear population most probably corresponding to re-populating osteoblasts. The suppression of RANK signalling may therefore generate a micro milieu favourable for malignant transformation.
In osteoporosis, denosumab treatment leads to significant increase in bone density; up to now no cases have been described of malignant tumors in patients treated with denosumab for osteoporosis. GCTB and osteoporosis are treated with different doses of denosumab. In osteoporosis 60 mg of denosumab is administered in a subcutaneous injection every six months. For treatment of GCTB a loading dose of 360 mg may be administered, followed by a subcutaneous injection of 120 mg every 4 weeks. The prescribed dose for GCTB is therefore estimated 12-times higher than the dosage used for treatment of osteoporosis. Since the approval for treatment of GCTB there have been at least 15 described cases of malignant transformation of GCTB in association with denosumab treatment10,20–26. Due to these reports the question arises whether the sarcoma is clonally linked to the primary tumor. In patient one we detected an ARID2 mutation limited to the recurrence of the GCTB after denosumab treatment. This finding suggests that mutated ARID2 is a marker during tumor progression under denosumab treatment in this H3F3A-mutated GCTB, although no sarcomatous transformation is present. In line with this finding is that ARID2 was identified to play a critical role in the differentiation of osteoblasts and that a mutation may interfere in this process27. The second patient reported was characterized by a persisting H3F3A mutation in the relapse as well as in the osteosarcoma arising in the sacrum. This finding points to a clonal evolution of the sarcoma under denosumab treatment; the H3F3A mutation can be regarded as a clonal marker in this case. In rare cases, H3F3A mutations have been described in osteosarcoma of the epiphyseal region of mostly older patients as shown by Koelsche et al.28. This finding is in line with a possible transformation of a pre-existing GCTB completely overrun by the sarcoma. In contrast, in patient three, a different mutational profile during progression emerged regarding the H3F3A mutation. The initial GCTB in the biopsy and in the recurrence was H3F3A-mutated, while the sarcoma was negative for this mutation as shown by sequencing and immunohistochemical staining. However, the recurrence of the GCTB and the sarcoma revealed an overlapping mutation for FGFR1, which was not present in the first biopsy. In addition, we detected a mutation in AKT2 and NRAS in the sarcoma. This may point to the evolution of a high-grade sarcoma from a H3F3A-negative, but FGFR1-positive subclone with acquisition of additional mutations in AKT2 and NRAS during tumor progression. One explanation is a transformation of the H3F3A-negative mononuclear cells residing in the tumor after denosumab treatment. Although the detected mutations in NRAS and AKT2 are intronic in the presented GCTB with no effect on the cDNA level these two genes have been shown to play a role in bone physiology and osteosarcomas. While NRAS mutations have been described in dysplastic bone formation29, AKT2 has been shown to play a role in tumor growth by inhibiting cisplatin-induced apoptosis in primary osteosarcomas30,31. Furthermore, Zhu et al. described an enhanced expression of AKT2 in osteosarcoma and that this finding is associated with a more aggressive clinical behaviour and worse outcome32.
Based on our analysis we cannot determine whether or not the transformation is a spontaneous event and occasionally associated with denosumab treatment. Large studies with a total of 2315 patients with GCTB have shown a cumulative incidence of primary malignant giant cell tumor of Bone (PMGCTB) of 1.6% in GCTB compared with 2.4% for secondary malignant giant cell tumor of bone (SMGCTB) following radiotherapy33. PMGCTB usually occurs next to an area of benign GCTB whereas SMGCTB occurs superimposed on a previously treated benign GCTB34. Several studies showed that patients with PMGCTB were of older age compared to patients with SMGCTB34,35. The clinical presentation of PMGCTB and SMGCTB is comparable36. Radiologically PMGCTB is often not distinguishable from benign GCTB whereas SMGCTB often presents findings suspicious of malignancy35.
In a further study on 532 patients receiving denosumab the number of patients with sarcomatous transformation was limited to four patients (1%)26.
Scotto di Carlo et al. reported in a recent study that GCTB shows a more malignant phenotype in a patient with Paget disease of bone which further points to malignant behaviour of GCTB depending on further co-factors37.
Whether the patients reported in literature with sarcomas after denosumab treatment fall in the category of being spontaneously transformed or being associated with denosumab therapy is yet not clear since 12 of them did not receive additional radiotherapy.
In conclusion, our findings point to different molecular profiles of GCTB associated with denosumab treatment and raise the question whether these events are spontaneous or associated with denosumab treatment. To clarify this question, more studies should be performed of GCTB in progression with and without denosumab treatment excluding those patients who received radiotherapy.
Supplementary Information
Supplementary Information.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-021-85319-x.
Acknowledgements
Case 3 was presented at the 89th spring meeting of the Arbeitsgemeinschaft Knochentumoren (AGKT; e.V.) in Heidelberg in 2017.
Author contributions
M.H., K.M., R.M., T.F.E.B. G.M. and P.M. conceived the experiments and analysed the data. M.H. and T.F.E.B. conducted the experiments. A.v.B., M.S., P.R, L.A-T, and B.L. collected material and primary data. M.H., K.M. and T.F.E.B. wrote the manuscript. M.H. and T.F.E.B., designed the figures and tables. All authors reviewed the manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | DENOSUMAB | DrugsGivenReaction | CC BY | 33707617 | 19,050,694 | 2021-03-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sepsis'. | Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation.
Giant cell tumor of bone (GCTB) is a locally aggressive lesion of intermediate malignancy. Malignant transformation of GCTB is a rare event. In 2013, the humanized monoclonal antibody against receptor activator of nuclear factor-κb-Ligand (RANKL) denosumab was approved for treatment of advanced GCTB. Since then, several reports have questioned the role of denosumab during occasional malignant transformation of GCTB. We report on three patients with H3F3A-mutated GCTBs, treated with denosumab. The tissue samples were analysed by histomorphology, immunohistochemistry, and in two instances by next generation panel sequencing of samples before and after treatment. One patient had a mutation of ARID2 in the recurrence of the GCTB under treatment with denosumab. One patient developed a pleomorphic sarcoma and one an osteoblastic osteosarcoma during treatment. Sequencing revealed a persisting H3F3A mutation in the osteosarcoma while the pleomorphic sarcoma lost the H3F3A mutation; however, a FGFR1 mutation, both in the recurrence and in the pleomorphic sarcoma persisted. In addition, the pleomorphic sarcoma showed an AKT2 and a NRAS mutation. These data are inconclusive concerning the role denosumab plays in the event of malignant progression/transformation of GCTB and point to diverging pathways of tumor progression of GCTB associated with this treatment.
Introduction
Giant cell tumor of bone (GCTB) was first described by Jaffe et al.1 in 1940 and makes up about five percent of all primary bone lesions2,3; GCTB is typically located in the epiphyseal region of the long tubular bones such as the distal femur and the proximal tibia3,4. Based on the WHO-Classification for tumors of soft tissue and bone, GCTB is considered to be an aggressive and rarely metastasizing tumor and therefore is regarded as tumor of intermediate malignancy (ICD-O: 9250/1)5. Metastatic lesions most commonly occur in the lungs4,6. In rare cases, a high-grade malignant neoplasia is identified arising in GCTB (primary malignancy in GCTB or after previous radiotherapy (in both instances classified as ICD-O: 9250/3)).
Histologically, the GCTB mainly consists of three different cell types. These are the neoplastic spindle-shaped stromal cells that show enhanced synthesis of receptor activator of nuclear factor-κb ligand (RANKL) and the large multinucleated osteoclast-like giant cells and their monocytic precursors expressing the corresponding receptor, i.e., receptor activator of nuclear factor-κb (RANK)7,8. The stroma cells are the neoplastic component of GCTB and harbour a characteristic point mutation at the histone gene H3F3A leading to a substitution of glycine by tryptophan at position 34 (G34W). The increased synthesis of the RANKL by the neoplastic cells leads to enhanced bone resorption by the osteoclast-like giant cells through the RANK/RANKL signalling pathway, which in turn are responsible for the locally aggressive growth.
Intralesional curettage is the primary treatment option for GCTB6. The rate of local recurrence after intralesional curettage ranges from 30 to 40%3,9. Denosumab was first approved for the treatment of osteoporosis under the brand name PROLIA in 2010 and was later approved for the treatment of GCTB in 2013 under the brand name XGEVA. Denosumab is a humanized monoclonal IgG2-anti-RANK-Ligand-antibody. This monoclonal antibody binds to RANKL and inhibits the interaction between the spindle-like stromal cells and the osteoclast-like giant cells, and thereby prevents local bone resorption, thus mimicking the effect of osteoprotegerin, a physiological RANKL-antagonist6,7.
Clinical case presentation
Patient one is a female, first diagnosed with GCTB in 2015 at the age of 33. The tumor measured 12 cm and was located in the pelvis; she was treated by a complete (R0) resection. In 08/2016 a denosumab treatment was started (120 mg subcutaneously every 4th week) until 06/2017 due to recurrence in the pelvis confirmed by a biopsy. The patient is well and shows no further signs of progression.
Patient two is a male that was diagnosed with a tumor of the sacrum measuring 13 cm in 03/2014 at the age of 20. A biopsy was performed and the diagnosis of GCTB was confirmed by detection of the H3F3A G34W mutation. In 04/2014 an incomplete resection of the tumor with instillation of alcohol 90% was performed. A fistula, which developed shortly after the first surgery, was resected.
In 12/2014, nine months after resection of the GCTB, a recurrence was diagnosed and denosumab treatment was started with 120 mg every 4 weeks until 05/2016. In 2017 the patient underwent palliative surgery. A CT-Scan showed a large local recurrence and pulmonary as well as liver lesions highly suspicious of metastases. The tumor mass was resected in 07/2017 and a high-grade osteosarcoma with angioinvasion harbouring the H3F3A G34W mutation was diagnosed.
The patient died in 08/2017 due to tumor progression and sepsis.
Patient three, a woman, is a follow-up initially published by Aponte-Tinao et al.10 in 2015. These authors reported the case of a 20-year-old female who was first diagnosed with GCTB in 2009. The GCTB was located at the right proximal tibia and was treated by intralesional curettage. She was diagnosed with a recurrence of GCTB about one year later in 2010 and was treated by en-bloc resection. The following two years were uneventful until a follow-up CT-scan showed a second recurrence in 2013 and denosumab therapy was started. The first application was a subcutaneous dose of 360 mg followed by 120 mg subcutaneously every 4 weeks. About one year after beginning of treatment with denosumab, the patient noticed a palpable, painful mass in the popliteal fossa. A CT-Scan showed that the mass included two sections of different density. An open biopsy was performed and histologic workup showed a high-grade undifferentiated pleomorphic sarcoma besides the GCTB. Subsequently an above-knee amputation was performed. Several tissue blocks were available for further histological analysis of the resection specimen. The patient is well and shows no signs of progression.
Methods
The samples were analysed by conventional histology using haematoxylin–eosin (HE) staining of sections of paraffin-embedded tissue. Immunohistochemistry was performed as described using a mutation specific monoclonal antibody for detection of the H3F3A G34W mutation (Anti H3.3 G34W clone 31-1145-00; RevMab Biosciences, San Francisco, CA, USA; dilution 1:400); for detection of proliferation indices the Ki-67 antibody (M7240, Dako, Glostrup, Denmark; dilution 1:200) was applied11.
The alkaline phosphatase/RED detection system (Dako) was used for immunohistochemistry on formalin-fixed and paraffin-embedded tissue via the avidin–biotin-complex-method. The samples were pseudonymized according to the German law for correct usage of archival tissue for clinical research. The research was approved by the local ethics committee of the University of Ulm (reference 369/17) and was in compliance with the ethical principles of the World Medical Association Declaration of Helsinki. Informed consent was obtained from all patients.
Isolation of tumor DNA from FFPE tissue
For isolation of genomic DNA from the formalin fixed paraffin embedded (FFPE) tissue samples, 5 μm tissue slices were transferred to glass slides. To estimate the area containing the tumor, HE stained FFPE tissue slices (2 µm) were validated by an expert pathologist. The tumor-harbouring areas of the FFPE tissue were subjected to a DNA extraction procedure using the QIAamp DNA FFPE tissue kit (QIAGEN, Hilden, Germany) according to manufacturer’s instruction. DNA purity and concentration were determined fluorometrically (Qubit 2.0; Invitrogen, Carlsbad, CA, USA).
We further performed Sanger-Sequencing for H3F3A G34W for all tissue samples of patient 1 and patient 3. Gene sequencing (Sanger) was performed according to a diagnostic standard protocol. The cell line A498 was used as negative control. The graphs were generated with FinchTV 1.4.0 (Geospiza Inc., Seattle Washington, USA)12.
Next generation sequencing
For molecular characterization of both tumor tissue and ctDNA, we employed a targeted re-sequencing methodology using the GeneRead V2 chemistry (QIAGEN, Hilden, Germany) and a custom-made re-sequencing panel including primers for all exons of a panel of 37 genes (primer sequences and locations of target areas are available upon request). Target enrichment, amplicon processing, and library generation were performed according to the manufacturer’s instructions. For target enrichment, we included 10–40 ng (DNA from FFPE tumor and non-neoplastic tissue). Successful target enrichment and library generation was checked using the High Sensitivity DNA kit on a bioanalyzer device (Agilent, Santa Clara, CA, USA). Libraries were diluted to 10 pM solutions and the sequencing was performed on a MiSeq platform (Illumina, San Diego, CA, USA) using the V2 chemistry. Mean read depth on target region was 2000–8000-fold and 99% of bases were covered at 96–100% on average. The resulting fastq files were subjected to further analysis using the GeneRead web based analysis tool (http://ngsdataanalysis.sabiosciences.com/NGS2/), the Biomedical Workbench software package (QIAGEN, Hilden, Germany), and the Variant Studio software (Illumina, San Diego, CA, USA)13. All identified mutations were manually re-analyzed using the Integrated Genome Viewer Software (Broad Institute, MA, USA).
Single nucleotide polymorphisms (SNP) detected in non-tumor-tissue were excluded from further analysis.
Results
Patient 1
Morphology
Tissue blocks of the primary biopsy, the resection specimen, and the recurrence under denosumab therapy were available. Histological analysis of the biopsy and resection specimen showed a giant cell tumor with typical morphology, consisting of osteoclastic giant cells and a mononuclear spindle cell compartment. The primary tumor showed a strong positivity for the H3.3 G34W detecting antibody in the nuclei of the stromal compartment. Nuclei of osteoclastic giant cells were negative. A second mononuclear cell population was detected being negative for H3.3 G34W which most probably presents osteoclastic precursors. Ki-67 rate was about 5% in the mononuclear cell population. After treatment the tumor revealed a dramatic change in morphology. The number of H3.3 G34W-positive osteoblastic cells was greatly reduced; positive mononuclear cells were still detectable along strands of neoformated osteoid. We detected an intermingled spindle cell compartment negative for H3.3 G34W. The Ki-67 index dropped to less than 1% (Fig. 1). The presence of the H3F3A G34W mutation was further proven by Sanger sequencing.Figure 1 Morphology of Case 1. (A) Typical GCTB with osteoclastic giant cells and intermingled mononuclear cells before therapy (bar = 100 µm). Neoplastic mononuclear cells are positive in a H3F3A G34W staining in the nuclei (B) and about 5% of cells are Ki-67 positive (C). After denosumab therapy GCTB shows induction of neoformated osteoid and complete reduction of giant cells (D), while H3F3A G34W-positive cells are still present (E); insert shows H3F3A-negative spindle cells. Proliferation has dropped to 1% in a Ki67 staining (F).
Panel sequencing of microdissected tissue of the resected tumor and the biopsy of the recurrence revealed a mutation of ARID2 (chromosome 12; position (GRCh37) 46205208, c.292G > A; p.E98K) with an allele frequency of 48% in the tumor recurrence under denosumab treatment. Neither the non-tumorous tissue nor the GCTB before treatment with denosumab harboured this mutation.
Patient 2
Morphology
The biopsy and resection specimen revealed a GCTB with typical morphology of osteoclastic giant cells and mononuclear spindle cells. Ki-67 rate was about 5%. Immunochemistry and sequencing confirmed the diagnosis of GCTB with positive staining for the mutation H3F3A G34W. This diagnosis was verified by Sanger-Sequencing.
Morphology of the resected recurrence revealed a pleomorphic high-grade sarcoma with necrosis and presence of atypical mitotic figures. The sarcoma showed intermingled lace-like neoplastic osteoid and was classified as a high-grade osteosarcoma; an angioinvasion was present. The sarcoma harboured the H3F3A G34W mutation as shown by immunohistochemistry in all tumor cells and a Ki-67 index of 90% (Fig. 2). This presence of the mutation was further confirmed by Sanger sequencing for H3F3A G34W mutation.Figure 2 Morphology of Case 2. Typical morphology of GCTB with osteoclastic giant cells and mononuclear spindle cells (A) neoplastic mononuclear cells with positive H3F3A G34W staining (B) (bar = 100 µm). Staining for Ki-67 shows about 5% positive cells (C). The sarcoma showed presents with polymorphic tumor cells andatypical mitotic figures with necrosis intermingled lace-like neoplastic osteoid intermingled with necrotic bone. An atypical mitotic figure is shown in the insert (D). The sarcoma harboured the H3F3A G34W mutation (E) and had a high rate of Ki-67 (F).
Patient 3
Morphology
The morphology of this tumor has been described in details by Aponte et al.10. In brief, the initial GCTB revealed a typical morphology with osteoclastic giant cells and a mononuclear H3F3A G34W-positive neoplastic tumor population as shown by immunohistological staining and sequencing both of the primary tumor and the recurrence. The Ki-67 index was about 5%. The sarcoma after denosumab treatment showed a high-grade sarcoma (not otherwise specified) with spindle-like to pleomorphic tumor cells and extensive necrosis and a Ki-67 index of 50%.
The sarcoma was negative in an immunohistochemical staining with the monoclonal antibody for detection of H3F3A G34W.
Sequencing of DNA from microdissected tissue of the H3F3A G34W-negative tumor showed a very weak peak for a mutation-specific thymine that was below the detection threshold as shown in Fig. 3.Figure 3 Morphology of Case 3. (1) Biopsy. (2) Resection specimen. (3) Sarcoma. Typical GCTB with osteoclastic giant cells and intermingled mononuclear cells in the biopsy (1A) and the resection specimen (2A) as well as neoplastic mononuclear cells with positive H3F3A G34W staining in the nuclei (1B,2B) (bar = 100 µm). Staining for Ki-67 shows about 1% of positive cells (1C,2C). Sanger-Sequencing for H3F3A G34W shows the mutation specific thymine in tissue of the biopsy (1D) as well as the resection specimen (2D). The sarcoma showed spindle to pleomorphic tumor cells and extensive necrosis (3A) and a high Ki-67 index (3C), however it did not stain positive for H3F3A G34W (3B). Sanger-sequencing of DNA from microdissected tissue of the H3F3A G34W-negative tumor showed a very weak peak for a mutation-specific thymine (3D).
In the panel-sequencing we found a mutation of FGFR1 (chromosome 8; position (GRCh37) 38287303; c354G > A; p.E118) in the resection specimen of the GCTB and in the sarcoma with an allele frequency of 10%, which was not found in the biopsy. We found two additional mutations in the sarcoma tissue for AKT2 (chromosome 19; position (GRCh37) 40742052) and NRAS (chromosome 1; position (GRCh37) 115256669) with a frequency of 26% and 48%, respectively; these two mutations were not present in the initial biopsy or in the resection specimen (Fig. 4) and present intronic mutations with no effect on the protein structure. Supplementary Figs. 1 and 2 summarize the clinical and molecular findings.Figure 4 Summary of SNPs found in the different tissue samples (Case 3). SNPs in the resection: FGFR1 (chromosome 8; position (GRCh37) 38287303; c354G > A; p.E118). SNPs in the pleomorphic sarcoma: FGFR1 (chromosome 8; position (GRCh37) 38287303; c354G > A; p.E118); AKT2 (chromosome 19; position (GRCh37) 40742052); NRAS (chromosome 1; position (GRCh37) 115256669).
Discussion
GCTB is characterized by an enhanced paraneoplastic secretion of RANKL, leading to a shift of normal bone homeostasis to enforced bone resorption due to an increased number of induced non-neoplastic osteoclasts3,14. Denosumab was first approved for treatment of GCTB in 2013 in advanced stage and is a humanized monoclonal IgG2 antibody. Through specific binding to RANKL denosumab blocks the RANK/RANKL signalling. This treatment leads to striking changes in morphology of GCTB characterized by reduction of both, the neoplastic cell compartment and the osteoclasts14. Due to blockage of the RANK/RANKL axis enhanced osteoid neoformation of bone is observed by H3F3A-non-mutated osteoblasts and fibroblastoid spindle cells11.. Mak et al. showed that denosumab reduced the number of osteoclasts and RANKL secretion in vitro, however the neoplastic stromal cells continued to grow after reduction of denosumab, even though at a slower proliferation rate15. The authors conclude that after denosumab treatment the H3F3A-mutated tumor cell pool may reside in the tissue and be reactivated during recurrence15. Besides the role of the RANK axis in the control of bone remodelling and as a crucial factor in GCTB growth, RANKL has an important role for the differentiation of B and T cells as well as for the survival of dendritic cells16,17; by this mechanism, enhanced RANKL synthesis in GCTB may lead to immunosuppression and therefore promote neoplastic transformation18.
On the other hand, nuclear factor κb upregulation by enhanced RANK signalling is discussed to interfere with regulation of oncogenes18. It has been shown that RANKL upregulates the expression of semaphorin 3A20, and may thereby affect growth of cartilage and bone21. Furthermore, in a comparative proteome study of GCTB before and after denosumab therapy several differentially expressed proteins were identified including metalloproteinase 9 being downregulated after denosumab treatment19. Interestingly, we noted a reduction of proliferation of the GCTB after treatment in the recurrences of patient one, however we further detected a H3F3A-negative mononuclear population most probably corresponding to re-populating osteoblasts. The suppression of RANK signalling may therefore generate a micro milieu favourable for malignant transformation.
In osteoporosis, denosumab treatment leads to significant increase in bone density; up to now no cases have been described of malignant tumors in patients treated with denosumab for osteoporosis. GCTB and osteoporosis are treated with different doses of denosumab. In osteoporosis 60 mg of denosumab is administered in a subcutaneous injection every six months. For treatment of GCTB a loading dose of 360 mg may be administered, followed by a subcutaneous injection of 120 mg every 4 weeks. The prescribed dose for GCTB is therefore estimated 12-times higher than the dosage used for treatment of osteoporosis. Since the approval for treatment of GCTB there have been at least 15 described cases of malignant transformation of GCTB in association with denosumab treatment10,20–26. Due to these reports the question arises whether the sarcoma is clonally linked to the primary tumor. In patient one we detected an ARID2 mutation limited to the recurrence of the GCTB after denosumab treatment. This finding suggests that mutated ARID2 is a marker during tumor progression under denosumab treatment in this H3F3A-mutated GCTB, although no sarcomatous transformation is present. In line with this finding is that ARID2 was identified to play a critical role in the differentiation of osteoblasts and that a mutation may interfere in this process27. The second patient reported was characterized by a persisting H3F3A mutation in the relapse as well as in the osteosarcoma arising in the sacrum. This finding points to a clonal evolution of the sarcoma under denosumab treatment; the H3F3A mutation can be regarded as a clonal marker in this case. In rare cases, H3F3A mutations have been described in osteosarcoma of the epiphyseal region of mostly older patients as shown by Koelsche et al.28. This finding is in line with a possible transformation of a pre-existing GCTB completely overrun by the sarcoma. In contrast, in patient three, a different mutational profile during progression emerged regarding the H3F3A mutation. The initial GCTB in the biopsy and in the recurrence was H3F3A-mutated, while the sarcoma was negative for this mutation as shown by sequencing and immunohistochemical staining. However, the recurrence of the GCTB and the sarcoma revealed an overlapping mutation for FGFR1, which was not present in the first biopsy. In addition, we detected a mutation in AKT2 and NRAS in the sarcoma. This may point to the evolution of a high-grade sarcoma from a H3F3A-negative, but FGFR1-positive subclone with acquisition of additional mutations in AKT2 and NRAS during tumor progression. One explanation is a transformation of the H3F3A-negative mononuclear cells residing in the tumor after denosumab treatment. Although the detected mutations in NRAS and AKT2 are intronic in the presented GCTB with no effect on the cDNA level these two genes have been shown to play a role in bone physiology and osteosarcomas. While NRAS mutations have been described in dysplastic bone formation29, AKT2 has been shown to play a role in tumor growth by inhibiting cisplatin-induced apoptosis in primary osteosarcomas30,31. Furthermore, Zhu et al. described an enhanced expression of AKT2 in osteosarcoma and that this finding is associated with a more aggressive clinical behaviour and worse outcome32.
Based on our analysis we cannot determine whether or not the transformation is a spontaneous event and occasionally associated with denosumab treatment. Large studies with a total of 2315 patients with GCTB have shown a cumulative incidence of primary malignant giant cell tumor of Bone (PMGCTB) of 1.6% in GCTB compared with 2.4% for secondary malignant giant cell tumor of bone (SMGCTB) following radiotherapy33. PMGCTB usually occurs next to an area of benign GCTB whereas SMGCTB occurs superimposed on a previously treated benign GCTB34. Several studies showed that patients with PMGCTB were of older age compared to patients with SMGCTB34,35. The clinical presentation of PMGCTB and SMGCTB is comparable36. Radiologically PMGCTB is often not distinguishable from benign GCTB whereas SMGCTB often presents findings suspicious of malignancy35.
In a further study on 532 patients receiving denosumab the number of patients with sarcomatous transformation was limited to four patients (1%)26.
Scotto di Carlo et al. reported in a recent study that GCTB shows a more malignant phenotype in a patient with Paget disease of bone which further points to malignant behaviour of GCTB depending on further co-factors37.
Whether the patients reported in literature with sarcomas after denosumab treatment fall in the category of being spontaneously transformed or being associated with denosumab therapy is yet not clear since 12 of them did not receive additional radiotherapy.
In conclusion, our findings point to different molecular profiles of GCTB associated with denosumab treatment and raise the question whether these events are spontaneous or associated with denosumab treatment. To clarify this question, more studies should be performed of GCTB in progression with and without denosumab treatment excluding those patients who received radiotherapy.
Supplementary Information
Supplementary Information.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-021-85319-x.
Acknowledgements
Case 3 was presented at the 89th spring meeting of the Arbeitsgemeinschaft Knochentumoren (AGKT; e.V.) in Heidelberg in 2017.
Author contributions
M.H., K.M., R.M., T.F.E.B. G.M. and P.M. conceived the experiments and analysed the data. M.H. and T.F.E.B. conducted the experiments. A.v.B., M.S., P.R, L.A-T, and B.L. collected material and primary data. M.H., K.M. and T.F.E.B. wrote the manuscript. M.H. and T.F.E.B., designed the figures and tables. All authors reviewed the manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | DENOSUMAB | DrugsGivenReaction | CC BY | 33707617 | 19,050,694 | 2021-03-11 |
What was the outcome of reaction 'Osteosarcoma'? | Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation.
Giant cell tumor of bone (GCTB) is a locally aggressive lesion of intermediate malignancy. Malignant transformation of GCTB is a rare event. In 2013, the humanized monoclonal antibody against receptor activator of nuclear factor-κb-Ligand (RANKL) denosumab was approved for treatment of advanced GCTB. Since then, several reports have questioned the role of denosumab during occasional malignant transformation of GCTB. We report on three patients with H3F3A-mutated GCTBs, treated with denosumab. The tissue samples were analysed by histomorphology, immunohistochemistry, and in two instances by next generation panel sequencing of samples before and after treatment. One patient had a mutation of ARID2 in the recurrence of the GCTB under treatment with denosumab. One patient developed a pleomorphic sarcoma and one an osteoblastic osteosarcoma during treatment. Sequencing revealed a persisting H3F3A mutation in the osteosarcoma while the pleomorphic sarcoma lost the H3F3A mutation; however, a FGFR1 mutation, both in the recurrence and in the pleomorphic sarcoma persisted. In addition, the pleomorphic sarcoma showed an AKT2 and a NRAS mutation. These data are inconclusive concerning the role denosumab plays in the event of malignant progression/transformation of GCTB and point to diverging pathways of tumor progression of GCTB associated with this treatment.
Introduction
Giant cell tumor of bone (GCTB) was first described by Jaffe et al.1 in 1940 and makes up about five percent of all primary bone lesions2,3; GCTB is typically located in the epiphyseal region of the long tubular bones such as the distal femur and the proximal tibia3,4. Based on the WHO-Classification for tumors of soft tissue and bone, GCTB is considered to be an aggressive and rarely metastasizing tumor and therefore is regarded as tumor of intermediate malignancy (ICD-O: 9250/1)5. Metastatic lesions most commonly occur in the lungs4,6. In rare cases, a high-grade malignant neoplasia is identified arising in GCTB (primary malignancy in GCTB or after previous radiotherapy (in both instances classified as ICD-O: 9250/3)).
Histologically, the GCTB mainly consists of three different cell types. These are the neoplastic spindle-shaped stromal cells that show enhanced synthesis of receptor activator of nuclear factor-κb ligand (RANKL) and the large multinucleated osteoclast-like giant cells and their monocytic precursors expressing the corresponding receptor, i.e., receptor activator of nuclear factor-κb (RANK)7,8. The stroma cells are the neoplastic component of GCTB and harbour a characteristic point mutation at the histone gene H3F3A leading to a substitution of glycine by tryptophan at position 34 (G34W). The increased synthesis of the RANKL by the neoplastic cells leads to enhanced bone resorption by the osteoclast-like giant cells through the RANK/RANKL signalling pathway, which in turn are responsible for the locally aggressive growth.
Intralesional curettage is the primary treatment option for GCTB6. The rate of local recurrence after intralesional curettage ranges from 30 to 40%3,9. Denosumab was first approved for the treatment of osteoporosis under the brand name PROLIA in 2010 and was later approved for the treatment of GCTB in 2013 under the brand name XGEVA. Denosumab is a humanized monoclonal IgG2-anti-RANK-Ligand-antibody. This monoclonal antibody binds to RANKL and inhibits the interaction between the spindle-like stromal cells and the osteoclast-like giant cells, and thereby prevents local bone resorption, thus mimicking the effect of osteoprotegerin, a physiological RANKL-antagonist6,7.
Clinical case presentation
Patient one is a female, first diagnosed with GCTB in 2015 at the age of 33. The tumor measured 12 cm and was located in the pelvis; she was treated by a complete (R0) resection. In 08/2016 a denosumab treatment was started (120 mg subcutaneously every 4th week) until 06/2017 due to recurrence in the pelvis confirmed by a biopsy. The patient is well and shows no further signs of progression.
Patient two is a male that was diagnosed with a tumor of the sacrum measuring 13 cm in 03/2014 at the age of 20. A biopsy was performed and the diagnosis of GCTB was confirmed by detection of the H3F3A G34W mutation. In 04/2014 an incomplete resection of the tumor with instillation of alcohol 90% was performed. A fistula, which developed shortly after the first surgery, was resected.
In 12/2014, nine months after resection of the GCTB, a recurrence was diagnosed and denosumab treatment was started with 120 mg every 4 weeks until 05/2016. In 2017 the patient underwent palliative surgery. A CT-Scan showed a large local recurrence and pulmonary as well as liver lesions highly suspicious of metastases. The tumor mass was resected in 07/2017 and a high-grade osteosarcoma with angioinvasion harbouring the H3F3A G34W mutation was diagnosed.
The patient died in 08/2017 due to tumor progression and sepsis.
Patient three, a woman, is a follow-up initially published by Aponte-Tinao et al.10 in 2015. These authors reported the case of a 20-year-old female who was first diagnosed with GCTB in 2009. The GCTB was located at the right proximal tibia and was treated by intralesional curettage. She was diagnosed with a recurrence of GCTB about one year later in 2010 and was treated by en-bloc resection. The following two years were uneventful until a follow-up CT-scan showed a second recurrence in 2013 and denosumab therapy was started. The first application was a subcutaneous dose of 360 mg followed by 120 mg subcutaneously every 4 weeks. About one year after beginning of treatment with denosumab, the patient noticed a palpable, painful mass in the popliteal fossa. A CT-Scan showed that the mass included two sections of different density. An open biopsy was performed and histologic workup showed a high-grade undifferentiated pleomorphic sarcoma besides the GCTB. Subsequently an above-knee amputation was performed. Several tissue blocks were available for further histological analysis of the resection specimen. The patient is well and shows no signs of progression.
Methods
The samples were analysed by conventional histology using haematoxylin–eosin (HE) staining of sections of paraffin-embedded tissue. Immunohistochemistry was performed as described using a mutation specific monoclonal antibody for detection of the H3F3A G34W mutation (Anti H3.3 G34W clone 31-1145-00; RevMab Biosciences, San Francisco, CA, USA; dilution 1:400); for detection of proliferation indices the Ki-67 antibody (M7240, Dako, Glostrup, Denmark; dilution 1:200) was applied11.
The alkaline phosphatase/RED detection system (Dako) was used for immunohistochemistry on formalin-fixed and paraffin-embedded tissue via the avidin–biotin-complex-method. The samples were pseudonymized according to the German law for correct usage of archival tissue for clinical research. The research was approved by the local ethics committee of the University of Ulm (reference 369/17) and was in compliance with the ethical principles of the World Medical Association Declaration of Helsinki. Informed consent was obtained from all patients.
Isolation of tumor DNA from FFPE tissue
For isolation of genomic DNA from the formalin fixed paraffin embedded (FFPE) tissue samples, 5 μm tissue slices were transferred to glass slides. To estimate the area containing the tumor, HE stained FFPE tissue slices (2 µm) were validated by an expert pathologist. The tumor-harbouring areas of the FFPE tissue were subjected to a DNA extraction procedure using the QIAamp DNA FFPE tissue kit (QIAGEN, Hilden, Germany) according to manufacturer’s instruction. DNA purity and concentration were determined fluorometrically (Qubit 2.0; Invitrogen, Carlsbad, CA, USA).
We further performed Sanger-Sequencing for H3F3A G34W for all tissue samples of patient 1 and patient 3. Gene sequencing (Sanger) was performed according to a diagnostic standard protocol. The cell line A498 was used as negative control. The graphs were generated with FinchTV 1.4.0 (Geospiza Inc., Seattle Washington, USA)12.
Next generation sequencing
For molecular characterization of both tumor tissue and ctDNA, we employed a targeted re-sequencing methodology using the GeneRead V2 chemistry (QIAGEN, Hilden, Germany) and a custom-made re-sequencing panel including primers for all exons of a panel of 37 genes (primer sequences and locations of target areas are available upon request). Target enrichment, amplicon processing, and library generation were performed according to the manufacturer’s instructions. For target enrichment, we included 10–40 ng (DNA from FFPE tumor and non-neoplastic tissue). Successful target enrichment and library generation was checked using the High Sensitivity DNA kit on a bioanalyzer device (Agilent, Santa Clara, CA, USA). Libraries were diluted to 10 pM solutions and the sequencing was performed on a MiSeq platform (Illumina, San Diego, CA, USA) using the V2 chemistry. Mean read depth on target region was 2000–8000-fold and 99% of bases were covered at 96–100% on average. The resulting fastq files were subjected to further analysis using the GeneRead web based analysis tool (http://ngsdataanalysis.sabiosciences.com/NGS2/), the Biomedical Workbench software package (QIAGEN, Hilden, Germany), and the Variant Studio software (Illumina, San Diego, CA, USA)13. All identified mutations were manually re-analyzed using the Integrated Genome Viewer Software (Broad Institute, MA, USA).
Single nucleotide polymorphisms (SNP) detected in non-tumor-tissue were excluded from further analysis.
Results
Patient 1
Morphology
Tissue blocks of the primary biopsy, the resection specimen, and the recurrence under denosumab therapy were available. Histological analysis of the biopsy and resection specimen showed a giant cell tumor with typical morphology, consisting of osteoclastic giant cells and a mononuclear spindle cell compartment. The primary tumor showed a strong positivity for the H3.3 G34W detecting antibody in the nuclei of the stromal compartment. Nuclei of osteoclastic giant cells were negative. A second mononuclear cell population was detected being negative for H3.3 G34W which most probably presents osteoclastic precursors. Ki-67 rate was about 5% in the mononuclear cell population. After treatment the tumor revealed a dramatic change in morphology. The number of H3.3 G34W-positive osteoblastic cells was greatly reduced; positive mononuclear cells were still detectable along strands of neoformated osteoid. We detected an intermingled spindle cell compartment negative for H3.3 G34W. The Ki-67 index dropped to less than 1% (Fig. 1). The presence of the H3F3A G34W mutation was further proven by Sanger sequencing.Figure 1 Morphology of Case 1. (A) Typical GCTB with osteoclastic giant cells and intermingled mononuclear cells before therapy (bar = 100 µm). Neoplastic mononuclear cells are positive in a H3F3A G34W staining in the nuclei (B) and about 5% of cells are Ki-67 positive (C). After denosumab therapy GCTB shows induction of neoformated osteoid and complete reduction of giant cells (D), while H3F3A G34W-positive cells are still present (E); insert shows H3F3A-negative spindle cells. Proliferation has dropped to 1% in a Ki67 staining (F).
Panel sequencing of microdissected tissue of the resected tumor and the biopsy of the recurrence revealed a mutation of ARID2 (chromosome 12; position (GRCh37) 46205208, c.292G > A; p.E98K) with an allele frequency of 48% in the tumor recurrence under denosumab treatment. Neither the non-tumorous tissue nor the GCTB before treatment with denosumab harboured this mutation.
Patient 2
Morphology
The biopsy and resection specimen revealed a GCTB with typical morphology of osteoclastic giant cells and mononuclear spindle cells. Ki-67 rate was about 5%. Immunochemistry and sequencing confirmed the diagnosis of GCTB with positive staining for the mutation H3F3A G34W. This diagnosis was verified by Sanger-Sequencing.
Morphology of the resected recurrence revealed a pleomorphic high-grade sarcoma with necrosis and presence of atypical mitotic figures. The sarcoma showed intermingled lace-like neoplastic osteoid and was classified as a high-grade osteosarcoma; an angioinvasion was present. The sarcoma harboured the H3F3A G34W mutation as shown by immunohistochemistry in all tumor cells and a Ki-67 index of 90% (Fig. 2). This presence of the mutation was further confirmed by Sanger sequencing for H3F3A G34W mutation.Figure 2 Morphology of Case 2. Typical morphology of GCTB with osteoclastic giant cells and mononuclear spindle cells (A) neoplastic mononuclear cells with positive H3F3A G34W staining (B) (bar = 100 µm). Staining for Ki-67 shows about 5% positive cells (C). The sarcoma showed presents with polymorphic tumor cells andatypical mitotic figures with necrosis intermingled lace-like neoplastic osteoid intermingled with necrotic bone. An atypical mitotic figure is shown in the insert (D). The sarcoma harboured the H3F3A G34W mutation (E) and had a high rate of Ki-67 (F).
Patient 3
Morphology
The morphology of this tumor has been described in details by Aponte et al.10. In brief, the initial GCTB revealed a typical morphology with osteoclastic giant cells and a mononuclear H3F3A G34W-positive neoplastic tumor population as shown by immunohistological staining and sequencing both of the primary tumor and the recurrence. The Ki-67 index was about 5%. The sarcoma after denosumab treatment showed a high-grade sarcoma (not otherwise specified) with spindle-like to pleomorphic tumor cells and extensive necrosis and a Ki-67 index of 50%.
The sarcoma was negative in an immunohistochemical staining with the monoclonal antibody for detection of H3F3A G34W.
Sequencing of DNA from microdissected tissue of the H3F3A G34W-negative tumor showed a very weak peak for a mutation-specific thymine that was below the detection threshold as shown in Fig. 3.Figure 3 Morphology of Case 3. (1) Biopsy. (2) Resection specimen. (3) Sarcoma. Typical GCTB with osteoclastic giant cells and intermingled mononuclear cells in the biopsy (1A) and the resection specimen (2A) as well as neoplastic mononuclear cells with positive H3F3A G34W staining in the nuclei (1B,2B) (bar = 100 µm). Staining for Ki-67 shows about 1% of positive cells (1C,2C). Sanger-Sequencing for H3F3A G34W shows the mutation specific thymine in tissue of the biopsy (1D) as well as the resection specimen (2D). The sarcoma showed spindle to pleomorphic tumor cells and extensive necrosis (3A) and a high Ki-67 index (3C), however it did not stain positive for H3F3A G34W (3B). Sanger-sequencing of DNA from microdissected tissue of the H3F3A G34W-negative tumor showed a very weak peak for a mutation-specific thymine (3D).
In the panel-sequencing we found a mutation of FGFR1 (chromosome 8; position (GRCh37) 38287303; c354G > A; p.E118) in the resection specimen of the GCTB and in the sarcoma with an allele frequency of 10%, which was not found in the biopsy. We found two additional mutations in the sarcoma tissue for AKT2 (chromosome 19; position (GRCh37) 40742052) and NRAS (chromosome 1; position (GRCh37) 115256669) with a frequency of 26% and 48%, respectively; these two mutations were not present in the initial biopsy or in the resection specimen (Fig. 4) and present intronic mutations with no effect on the protein structure. Supplementary Figs. 1 and 2 summarize the clinical and molecular findings.Figure 4 Summary of SNPs found in the different tissue samples (Case 3). SNPs in the resection: FGFR1 (chromosome 8; position (GRCh37) 38287303; c354G > A; p.E118). SNPs in the pleomorphic sarcoma: FGFR1 (chromosome 8; position (GRCh37) 38287303; c354G > A; p.E118); AKT2 (chromosome 19; position (GRCh37) 40742052); NRAS (chromosome 1; position (GRCh37) 115256669).
Discussion
GCTB is characterized by an enhanced paraneoplastic secretion of RANKL, leading to a shift of normal bone homeostasis to enforced bone resorption due to an increased number of induced non-neoplastic osteoclasts3,14. Denosumab was first approved for treatment of GCTB in 2013 in advanced stage and is a humanized monoclonal IgG2 antibody. Through specific binding to RANKL denosumab blocks the RANK/RANKL signalling. This treatment leads to striking changes in morphology of GCTB characterized by reduction of both, the neoplastic cell compartment and the osteoclasts14. Due to blockage of the RANK/RANKL axis enhanced osteoid neoformation of bone is observed by H3F3A-non-mutated osteoblasts and fibroblastoid spindle cells11.. Mak et al. showed that denosumab reduced the number of osteoclasts and RANKL secretion in vitro, however the neoplastic stromal cells continued to grow after reduction of denosumab, even though at a slower proliferation rate15. The authors conclude that after denosumab treatment the H3F3A-mutated tumor cell pool may reside in the tissue and be reactivated during recurrence15. Besides the role of the RANK axis in the control of bone remodelling and as a crucial factor in GCTB growth, RANKL has an important role for the differentiation of B and T cells as well as for the survival of dendritic cells16,17; by this mechanism, enhanced RANKL synthesis in GCTB may lead to immunosuppression and therefore promote neoplastic transformation18.
On the other hand, nuclear factor κb upregulation by enhanced RANK signalling is discussed to interfere with regulation of oncogenes18. It has been shown that RANKL upregulates the expression of semaphorin 3A20, and may thereby affect growth of cartilage and bone21. Furthermore, in a comparative proteome study of GCTB before and after denosumab therapy several differentially expressed proteins were identified including metalloproteinase 9 being downregulated after denosumab treatment19. Interestingly, we noted a reduction of proliferation of the GCTB after treatment in the recurrences of patient one, however we further detected a H3F3A-negative mononuclear population most probably corresponding to re-populating osteoblasts. The suppression of RANK signalling may therefore generate a micro milieu favourable for malignant transformation.
In osteoporosis, denosumab treatment leads to significant increase in bone density; up to now no cases have been described of malignant tumors in patients treated with denosumab for osteoporosis. GCTB and osteoporosis are treated with different doses of denosumab. In osteoporosis 60 mg of denosumab is administered in a subcutaneous injection every six months. For treatment of GCTB a loading dose of 360 mg may be administered, followed by a subcutaneous injection of 120 mg every 4 weeks. The prescribed dose for GCTB is therefore estimated 12-times higher than the dosage used for treatment of osteoporosis. Since the approval for treatment of GCTB there have been at least 15 described cases of malignant transformation of GCTB in association with denosumab treatment10,20–26. Due to these reports the question arises whether the sarcoma is clonally linked to the primary tumor. In patient one we detected an ARID2 mutation limited to the recurrence of the GCTB after denosumab treatment. This finding suggests that mutated ARID2 is a marker during tumor progression under denosumab treatment in this H3F3A-mutated GCTB, although no sarcomatous transformation is present. In line with this finding is that ARID2 was identified to play a critical role in the differentiation of osteoblasts and that a mutation may interfere in this process27. The second patient reported was characterized by a persisting H3F3A mutation in the relapse as well as in the osteosarcoma arising in the sacrum. This finding points to a clonal evolution of the sarcoma under denosumab treatment; the H3F3A mutation can be regarded as a clonal marker in this case. In rare cases, H3F3A mutations have been described in osteosarcoma of the epiphyseal region of mostly older patients as shown by Koelsche et al.28. This finding is in line with a possible transformation of a pre-existing GCTB completely overrun by the sarcoma. In contrast, in patient three, a different mutational profile during progression emerged regarding the H3F3A mutation. The initial GCTB in the biopsy and in the recurrence was H3F3A-mutated, while the sarcoma was negative for this mutation as shown by sequencing and immunohistochemical staining. However, the recurrence of the GCTB and the sarcoma revealed an overlapping mutation for FGFR1, which was not present in the first biopsy. In addition, we detected a mutation in AKT2 and NRAS in the sarcoma. This may point to the evolution of a high-grade sarcoma from a H3F3A-negative, but FGFR1-positive subclone with acquisition of additional mutations in AKT2 and NRAS during tumor progression. One explanation is a transformation of the H3F3A-negative mononuclear cells residing in the tumor after denosumab treatment. Although the detected mutations in NRAS and AKT2 are intronic in the presented GCTB with no effect on the cDNA level these two genes have been shown to play a role in bone physiology and osteosarcomas. While NRAS mutations have been described in dysplastic bone formation29, AKT2 has been shown to play a role in tumor growth by inhibiting cisplatin-induced apoptosis in primary osteosarcomas30,31. Furthermore, Zhu et al. described an enhanced expression of AKT2 in osteosarcoma and that this finding is associated with a more aggressive clinical behaviour and worse outcome32.
Based on our analysis we cannot determine whether or not the transformation is a spontaneous event and occasionally associated with denosumab treatment. Large studies with a total of 2315 patients with GCTB have shown a cumulative incidence of primary malignant giant cell tumor of Bone (PMGCTB) of 1.6% in GCTB compared with 2.4% for secondary malignant giant cell tumor of bone (SMGCTB) following radiotherapy33. PMGCTB usually occurs next to an area of benign GCTB whereas SMGCTB occurs superimposed on a previously treated benign GCTB34. Several studies showed that patients with PMGCTB were of older age compared to patients with SMGCTB34,35. The clinical presentation of PMGCTB and SMGCTB is comparable36. Radiologically PMGCTB is often not distinguishable from benign GCTB whereas SMGCTB often presents findings suspicious of malignancy35.
In a further study on 532 patients receiving denosumab the number of patients with sarcomatous transformation was limited to four patients (1%)26.
Scotto di Carlo et al. reported in a recent study that GCTB shows a more malignant phenotype in a patient with Paget disease of bone which further points to malignant behaviour of GCTB depending on further co-factors37.
Whether the patients reported in literature with sarcomas after denosumab treatment fall in the category of being spontaneously transformed or being associated with denosumab therapy is yet not clear since 12 of them did not receive additional radiotherapy.
In conclusion, our findings point to different molecular profiles of GCTB associated with denosumab treatment and raise the question whether these events are spontaneous or associated with denosumab treatment. To clarify this question, more studies should be performed of GCTB in progression with and without denosumab treatment excluding those patients who received radiotherapy.
Supplementary Information
Supplementary Information.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-021-85319-x.
Acknowledgements
Case 3 was presented at the 89th spring meeting of the Arbeitsgemeinschaft Knochentumoren (AGKT; e.V.) in Heidelberg in 2017.
Author contributions
M.H., K.M., R.M., T.F.E.B. G.M. and P.M. conceived the experiments and analysed the data. M.H. and T.F.E.B. conducted the experiments. A.v.B., M.S., P.R, L.A-T, and B.L. collected material and primary data. M.H., K.M. and T.F.E.B. wrote the manuscript. M.H. and T.F.E.B., designed the figures and tables. All authors reviewed the manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Fatal | ReactionOutcome | CC BY | 33707617 | 19,050,694 | 2021-03-11 |
What was the outcome of reaction 'Sepsis'? | Profiling of three H3F3A-mutated and denosumab-treated giant cell tumors of bone points to diverging pathways during progression and malignant transformation.
Giant cell tumor of bone (GCTB) is a locally aggressive lesion of intermediate malignancy. Malignant transformation of GCTB is a rare event. In 2013, the humanized monoclonal antibody against receptor activator of nuclear factor-κb-Ligand (RANKL) denosumab was approved for treatment of advanced GCTB. Since then, several reports have questioned the role of denosumab during occasional malignant transformation of GCTB. We report on three patients with H3F3A-mutated GCTBs, treated with denosumab. The tissue samples were analysed by histomorphology, immunohistochemistry, and in two instances by next generation panel sequencing of samples before and after treatment. One patient had a mutation of ARID2 in the recurrence of the GCTB under treatment with denosumab. One patient developed a pleomorphic sarcoma and one an osteoblastic osteosarcoma during treatment. Sequencing revealed a persisting H3F3A mutation in the osteosarcoma while the pleomorphic sarcoma lost the H3F3A mutation; however, a FGFR1 mutation, both in the recurrence and in the pleomorphic sarcoma persisted. In addition, the pleomorphic sarcoma showed an AKT2 and a NRAS mutation. These data are inconclusive concerning the role denosumab plays in the event of malignant progression/transformation of GCTB and point to diverging pathways of tumor progression of GCTB associated with this treatment.
Introduction
Giant cell tumor of bone (GCTB) was first described by Jaffe et al.1 in 1940 and makes up about five percent of all primary bone lesions2,3; GCTB is typically located in the epiphyseal region of the long tubular bones such as the distal femur and the proximal tibia3,4. Based on the WHO-Classification for tumors of soft tissue and bone, GCTB is considered to be an aggressive and rarely metastasizing tumor and therefore is regarded as tumor of intermediate malignancy (ICD-O: 9250/1)5. Metastatic lesions most commonly occur in the lungs4,6. In rare cases, a high-grade malignant neoplasia is identified arising in GCTB (primary malignancy in GCTB or after previous radiotherapy (in both instances classified as ICD-O: 9250/3)).
Histologically, the GCTB mainly consists of three different cell types. These are the neoplastic spindle-shaped stromal cells that show enhanced synthesis of receptor activator of nuclear factor-κb ligand (RANKL) and the large multinucleated osteoclast-like giant cells and their monocytic precursors expressing the corresponding receptor, i.e., receptor activator of nuclear factor-κb (RANK)7,8. The stroma cells are the neoplastic component of GCTB and harbour a characteristic point mutation at the histone gene H3F3A leading to a substitution of glycine by tryptophan at position 34 (G34W). The increased synthesis of the RANKL by the neoplastic cells leads to enhanced bone resorption by the osteoclast-like giant cells through the RANK/RANKL signalling pathway, which in turn are responsible for the locally aggressive growth.
Intralesional curettage is the primary treatment option for GCTB6. The rate of local recurrence after intralesional curettage ranges from 30 to 40%3,9. Denosumab was first approved for the treatment of osteoporosis under the brand name PROLIA in 2010 and was later approved for the treatment of GCTB in 2013 under the brand name XGEVA. Denosumab is a humanized monoclonal IgG2-anti-RANK-Ligand-antibody. This monoclonal antibody binds to RANKL and inhibits the interaction between the spindle-like stromal cells and the osteoclast-like giant cells, and thereby prevents local bone resorption, thus mimicking the effect of osteoprotegerin, a physiological RANKL-antagonist6,7.
Clinical case presentation
Patient one is a female, first diagnosed with GCTB in 2015 at the age of 33. The tumor measured 12 cm and was located in the pelvis; she was treated by a complete (R0) resection. In 08/2016 a denosumab treatment was started (120 mg subcutaneously every 4th week) until 06/2017 due to recurrence in the pelvis confirmed by a biopsy. The patient is well and shows no further signs of progression.
Patient two is a male that was diagnosed with a tumor of the sacrum measuring 13 cm in 03/2014 at the age of 20. A biopsy was performed and the diagnosis of GCTB was confirmed by detection of the H3F3A G34W mutation. In 04/2014 an incomplete resection of the tumor with instillation of alcohol 90% was performed. A fistula, which developed shortly after the first surgery, was resected.
In 12/2014, nine months after resection of the GCTB, a recurrence was diagnosed and denosumab treatment was started with 120 mg every 4 weeks until 05/2016. In 2017 the patient underwent palliative surgery. A CT-Scan showed a large local recurrence and pulmonary as well as liver lesions highly suspicious of metastases. The tumor mass was resected in 07/2017 and a high-grade osteosarcoma with angioinvasion harbouring the H3F3A G34W mutation was diagnosed.
The patient died in 08/2017 due to tumor progression and sepsis.
Patient three, a woman, is a follow-up initially published by Aponte-Tinao et al.10 in 2015. These authors reported the case of a 20-year-old female who was first diagnosed with GCTB in 2009. The GCTB was located at the right proximal tibia and was treated by intralesional curettage. She was diagnosed with a recurrence of GCTB about one year later in 2010 and was treated by en-bloc resection. The following two years were uneventful until a follow-up CT-scan showed a second recurrence in 2013 and denosumab therapy was started. The first application was a subcutaneous dose of 360 mg followed by 120 mg subcutaneously every 4 weeks. About one year after beginning of treatment with denosumab, the patient noticed a palpable, painful mass in the popliteal fossa. A CT-Scan showed that the mass included two sections of different density. An open biopsy was performed and histologic workup showed a high-grade undifferentiated pleomorphic sarcoma besides the GCTB. Subsequently an above-knee amputation was performed. Several tissue blocks were available for further histological analysis of the resection specimen. The patient is well and shows no signs of progression.
Methods
The samples were analysed by conventional histology using haematoxylin–eosin (HE) staining of sections of paraffin-embedded tissue. Immunohistochemistry was performed as described using a mutation specific monoclonal antibody for detection of the H3F3A G34W mutation (Anti H3.3 G34W clone 31-1145-00; RevMab Biosciences, San Francisco, CA, USA; dilution 1:400); for detection of proliferation indices the Ki-67 antibody (M7240, Dako, Glostrup, Denmark; dilution 1:200) was applied11.
The alkaline phosphatase/RED detection system (Dako) was used for immunohistochemistry on formalin-fixed and paraffin-embedded tissue via the avidin–biotin-complex-method. The samples were pseudonymized according to the German law for correct usage of archival tissue for clinical research. The research was approved by the local ethics committee of the University of Ulm (reference 369/17) and was in compliance with the ethical principles of the World Medical Association Declaration of Helsinki. Informed consent was obtained from all patients.
Isolation of tumor DNA from FFPE tissue
For isolation of genomic DNA from the formalin fixed paraffin embedded (FFPE) tissue samples, 5 μm tissue slices were transferred to glass slides. To estimate the area containing the tumor, HE stained FFPE tissue slices (2 µm) were validated by an expert pathologist. The tumor-harbouring areas of the FFPE tissue were subjected to a DNA extraction procedure using the QIAamp DNA FFPE tissue kit (QIAGEN, Hilden, Germany) according to manufacturer’s instruction. DNA purity and concentration were determined fluorometrically (Qubit 2.0; Invitrogen, Carlsbad, CA, USA).
We further performed Sanger-Sequencing for H3F3A G34W for all tissue samples of patient 1 and patient 3. Gene sequencing (Sanger) was performed according to a diagnostic standard protocol. The cell line A498 was used as negative control. The graphs were generated with FinchTV 1.4.0 (Geospiza Inc., Seattle Washington, USA)12.
Next generation sequencing
For molecular characterization of both tumor tissue and ctDNA, we employed a targeted re-sequencing methodology using the GeneRead V2 chemistry (QIAGEN, Hilden, Germany) and a custom-made re-sequencing panel including primers for all exons of a panel of 37 genes (primer sequences and locations of target areas are available upon request). Target enrichment, amplicon processing, and library generation were performed according to the manufacturer’s instructions. For target enrichment, we included 10–40 ng (DNA from FFPE tumor and non-neoplastic tissue). Successful target enrichment and library generation was checked using the High Sensitivity DNA kit on a bioanalyzer device (Agilent, Santa Clara, CA, USA). Libraries were diluted to 10 pM solutions and the sequencing was performed on a MiSeq platform (Illumina, San Diego, CA, USA) using the V2 chemistry. Mean read depth on target region was 2000–8000-fold and 99% of bases were covered at 96–100% on average. The resulting fastq files were subjected to further analysis using the GeneRead web based analysis tool (http://ngsdataanalysis.sabiosciences.com/NGS2/), the Biomedical Workbench software package (QIAGEN, Hilden, Germany), and the Variant Studio software (Illumina, San Diego, CA, USA)13. All identified mutations were manually re-analyzed using the Integrated Genome Viewer Software (Broad Institute, MA, USA).
Single nucleotide polymorphisms (SNP) detected in non-tumor-tissue were excluded from further analysis.
Results
Patient 1
Morphology
Tissue blocks of the primary biopsy, the resection specimen, and the recurrence under denosumab therapy were available. Histological analysis of the biopsy and resection specimen showed a giant cell tumor with typical morphology, consisting of osteoclastic giant cells and a mononuclear spindle cell compartment. The primary tumor showed a strong positivity for the H3.3 G34W detecting antibody in the nuclei of the stromal compartment. Nuclei of osteoclastic giant cells were negative. A second mononuclear cell population was detected being negative for H3.3 G34W which most probably presents osteoclastic precursors. Ki-67 rate was about 5% in the mononuclear cell population. After treatment the tumor revealed a dramatic change in morphology. The number of H3.3 G34W-positive osteoblastic cells was greatly reduced; positive mononuclear cells were still detectable along strands of neoformated osteoid. We detected an intermingled spindle cell compartment negative for H3.3 G34W. The Ki-67 index dropped to less than 1% (Fig. 1). The presence of the H3F3A G34W mutation was further proven by Sanger sequencing.Figure 1 Morphology of Case 1. (A) Typical GCTB with osteoclastic giant cells and intermingled mononuclear cells before therapy (bar = 100 µm). Neoplastic mononuclear cells are positive in a H3F3A G34W staining in the nuclei (B) and about 5% of cells are Ki-67 positive (C). After denosumab therapy GCTB shows induction of neoformated osteoid and complete reduction of giant cells (D), while H3F3A G34W-positive cells are still present (E); insert shows H3F3A-negative spindle cells. Proliferation has dropped to 1% in a Ki67 staining (F).
Panel sequencing of microdissected tissue of the resected tumor and the biopsy of the recurrence revealed a mutation of ARID2 (chromosome 12; position (GRCh37) 46205208, c.292G > A; p.E98K) with an allele frequency of 48% in the tumor recurrence under denosumab treatment. Neither the non-tumorous tissue nor the GCTB before treatment with denosumab harboured this mutation.
Patient 2
Morphology
The biopsy and resection specimen revealed a GCTB with typical morphology of osteoclastic giant cells and mononuclear spindle cells. Ki-67 rate was about 5%. Immunochemistry and sequencing confirmed the diagnosis of GCTB with positive staining for the mutation H3F3A G34W. This diagnosis was verified by Sanger-Sequencing.
Morphology of the resected recurrence revealed a pleomorphic high-grade sarcoma with necrosis and presence of atypical mitotic figures. The sarcoma showed intermingled lace-like neoplastic osteoid and was classified as a high-grade osteosarcoma; an angioinvasion was present. The sarcoma harboured the H3F3A G34W mutation as shown by immunohistochemistry in all tumor cells and a Ki-67 index of 90% (Fig. 2). This presence of the mutation was further confirmed by Sanger sequencing for H3F3A G34W mutation.Figure 2 Morphology of Case 2. Typical morphology of GCTB with osteoclastic giant cells and mononuclear spindle cells (A) neoplastic mononuclear cells with positive H3F3A G34W staining (B) (bar = 100 µm). Staining for Ki-67 shows about 5% positive cells (C). The sarcoma showed presents with polymorphic tumor cells andatypical mitotic figures with necrosis intermingled lace-like neoplastic osteoid intermingled with necrotic bone. An atypical mitotic figure is shown in the insert (D). The sarcoma harboured the H3F3A G34W mutation (E) and had a high rate of Ki-67 (F).
Patient 3
Morphology
The morphology of this tumor has been described in details by Aponte et al.10. In brief, the initial GCTB revealed a typical morphology with osteoclastic giant cells and a mononuclear H3F3A G34W-positive neoplastic tumor population as shown by immunohistological staining and sequencing both of the primary tumor and the recurrence. The Ki-67 index was about 5%. The sarcoma after denosumab treatment showed a high-grade sarcoma (not otherwise specified) with spindle-like to pleomorphic tumor cells and extensive necrosis and a Ki-67 index of 50%.
The sarcoma was negative in an immunohistochemical staining with the monoclonal antibody for detection of H3F3A G34W.
Sequencing of DNA from microdissected tissue of the H3F3A G34W-negative tumor showed a very weak peak for a mutation-specific thymine that was below the detection threshold as shown in Fig. 3.Figure 3 Morphology of Case 3. (1) Biopsy. (2) Resection specimen. (3) Sarcoma. Typical GCTB with osteoclastic giant cells and intermingled mononuclear cells in the biopsy (1A) and the resection specimen (2A) as well as neoplastic mononuclear cells with positive H3F3A G34W staining in the nuclei (1B,2B) (bar = 100 µm). Staining for Ki-67 shows about 1% of positive cells (1C,2C). Sanger-Sequencing for H3F3A G34W shows the mutation specific thymine in tissue of the biopsy (1D) as well as the resection specimen (2D). The sarcoma showed spindle to pleomorphic tumor cells and extensive necrosis (3A) and a high Ki-67 index (3C), however it did not stain positive for H3F3A G34W (3B). Sanger-sequencing of DNA from microdissected tissue of the H3F3A G34W-negative tumor showed a very weak peak for a mutation-specific thymine (3D).
In the panel-sequencing we found a mutation of FGFR1 (chromosome 8; position (GRCh37) 38287303; c354G > A; p.E118) in the resection specimen of the GCTB and in the sarcoma with an allele frequency of 10%, which was not found in the biopsy. We found two additional mutations in the sarcoma tissue for AKT2 (chromosome 19; position (GRCh37) 40742052) and NRAS (chromosome 1; position (GRCh37) 115256669) with a frequency of 26% and 48%, respectively; these two mutations were not present in the initial biopsy or in the resection specimen (Fig. 4) and present intronic mutations with no effect on the protein structure. Supplementary Figs. 1 and 2 summarize the clinical and molecular findings.Figure 4 Summary of SNPs found in the different tissue samples (Case 3). SNPs in the resection: FGFR1 (chromosome 8; position (GRCh37) 38287303; c354G > A; p.E118). SNPs in the pleomorphic sarcoma: FGFR1 (chromosome 8; position (GRCh37) 38287303; c354G > A; p.E118); AKT2 (chromosome 19; position (GRCh37) 40742052); NRAS (chromosome 1; position (GRCh37) 115256669).
Discussion
GCTB is characterized by an enhanced paraneoplastic secretion of RANKL, leading to a shift of normal bone homeostasis to enforced bone resorption due to an increased number of induced non-neoplastic osteoclasts3,14. Denosumab was first approved for treatment of GCTB in 2013 in advanced stage and is a humanized monoclonal IgG2 antibody. Through specific binding to RANKL denosumab blocks the RANK/RANKL signalling. This treatment leads to striking changes in morphology of GCTB characterized by reduction of both, the neoplastic cell compartment and the osteoclasts14. Due to blockage of the RANK/RANKL axis enhanced osteoid neoformation of bone is observed by H3F3A-non-mutated osteoblasts and fibroblastoid spindle cells11.. Mak et al. showed that denosumab reduced the number of osteoclasts and RANKL secretion in vitro, however the neoplastic stromal cells continued to grow after reduction of denosumab, even though at a slower proliferation rate15. The authors conclude that after denosumab treatment the H3F3A-mutated tumor cell pool may reside in the tissue and be reactivated during recurrence15. Besides the role of the RANK axis in the control of bone remodelling and as a crucial factor in GCTB growth, RANKL has an important role for the differentiation of B and T cells as well as for the survival of dendritic cells16,17; by this mechanism, enhanced RANKL synthesis in GCTB may lead to immunosuppression and therefore promote neoplastic transformation18.
On the other hand, nuclear factor κb upregulation by enhanced RANK signalling is discussed to interfere with regulation of oncogenes18. It has been shown that RANKL upregulates the expression of semaphorin 3A20, and may thereby affect growth of cartilage and bone21. Furthermore, in a comparative proteome study of GCTB before and after denosumab therapy several differentially expressed proteins were identified including metalloproteinase 9 being downregulated after denosumab treatment19. Interestingly, we noted a reduction of proliferation of the GCTB after treatment in the recurrences of patient one, however we further detected a H3F3A-negative mononuclear population most probably corresponding to re-populating osteoblasts. The suppression of RANK signalling may therefore generate a micro milieu favourable for malignant transformation.
In osteoporosis, denosumab treatment leads to significant increase in bone density; up to now no cases have been described of malignant tumors in patients treated with denosumab for osteoporosis. GCTB and osteoporosis are treated with different doses of denosumab. In osteoporosis 60 mg of denosumab is administered in a subcutaneous injection every six months. For treatment of GCTB a loading dose of 360 mg may be administered, followed by a subcutaneous injection of 120 mg every 4 weeks. The prescribed dose for GCTB is therefore estimated 12-times higher than the dosage used for treatment of osteoporosis. Since the approval for treatment of GCTB there have been at least 15 described cases of malignant transformation of GCTB in association with denosumab treatment10,20–26. Due to these reports the question arises whether the sarcoma is clonally linked to the primary tumor. In patient one we detected an ARID2 mutation limited to the recurrence of the GCTB after denosumab treatment. This finding suggests that mutated ARID2 is a marker during tumor progression under denosumab treatment in this H3F3A-mutated GCTB, although no sarcomatous transformation is present. In line with this finding is that ARID2 was identified to play a critical role in the differentiation of osteoblasts and that a mutation may interfere in this process27. The second patient reported was characterized by a persisting H3F3A mutation in the relapse as well as in the osteosarcoma arising in the sacrum. This finding points to a clonal evolution of the sarcoma under denosumab treatment; the H3F3A mutation can be regarded as a clonal marker in this case. In rare cases, H3F3A mutations have been described in osteosarcoma of the epiphyseal region of mostly older patients as shown by Koelsche et al.28. This finding is in line with a possible transformation of a pre-existing GCTB completely overrun by the sarcoma. In contrast, in patient three, a different mutational profile during progression emerged regarding the H3F3A mutation. The initial GCTB in the biopsy and in the recurrence was H3F3A-mutated, while the sarcoma was negative for this mutation as shown by sequencing and immunohistochemical staining. However, the recurrence of the GCTB and the sarcoma revealed an overlapping mutation for FGFR1, which was not present in the first biopsy. In addition, we detected a mutation in AKT2 and NRAS in the sarcoma. This may point to the evolution of a high-grade sarcoma from a H3F3A-negative, but FGFR1-positive subclone with acquisition of additional mutations in AKT2 and NRAS during tumor progression. One explanation is a transformation of the H3F3A-negative mononuclear cells residing in the tumor after denosumab treatment. Although the detected mutations in NRAS and AKT2 are intronic in the presented GCTB with no effect on the cDNA level these two genes have been shown to play a role in bone physiology and osteosarcomas. While NRAS mutations have been described in dysplastic bone formation29, AKT2 has been shown to play a role in tumor growth by inhibiting cisplatin-induced apoptosis in primary osteosarcomas30,31. Furthermore, Zhu et al. described an enhanced expression of AKT2 in osteosarcoma and that this finding is associated with a more aggressive clinical behaviour and worse outcome32.
Based on our analysis we cannot determine whether or not the transformation is a spontaneous event and occasionally associated with denosumab treatment. Large studies with a total of 2315 patients with GCTB have shown a cumulative incidence of primary malignant giant cell tumor of Bone (PMGCTB) of 1.6% in GCTB compared with 2.4% for secondary malignant giant cell tumor of bone (SMGCTB) following radiotherapy33. PMGCTB usually occurs next to an area of benign GCTB whereas SMGCTB occurs superimposed on a previously treated benign GCTB34. Several studies showed that patients with PMGCTB were of older age compared to patients with SMGCTB34,35. The clinical presentation of PMGCTB and SMGCTB is comparable36. Radiologically PMGCTB is often not distinguishable from benign GCTB whereas SMGCTB often presents findings suspicious of malignancy35.
In a further study on 532 patients receiving denosumab the number of patients with sarcomatous transformation was limited to four patients (1%)26.
Scotto di Carlo et al. reported in a recent study that GCTB shows a more malignant phenotype in a patient with Paget disease of bone which further points to malignant behaviour of GCTB depending on further co-factors37.
Whether the patients reported in literature with sarcomas after denosumab treatment fall in the category of being spontaneously transformed or being associated with denosumab therapy is yet not clear since 12 of them did not receive additional radiotherapy.
In conclusion, our findings point to different molecular profiles of GCTB associated with denosumab treatment and raise the question whether these events are spontaneous or associated with denosumab treatment. To clarify this question, more studies should be performed of GCTB in progression with and without denosumab treatment excluding those patients who received radiotherapy.
Supplementary Information
Supplementary Information.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-021-85319-x.
Acknowledgements
Case 3 was presented at the 89th spring meeting of the Arbeitsgemeinschaft Knochentumoren (AGKT; e.V.) in Heidelberg in 2017.
Author contributions
M.H., K.M., R.M., T.F.E.B. G.M. and P.M. conceived the experiments and analysed the data. M.H. and T.F.E.B. conducted the experiments. A.v.B., M.S., P.R, L.A-T, and B.L. collected material and primary data. M.H., K.M. and T.F.E.B. wrote the manuscript. M.H. and T.F.E.B., designed the figures and tables. All authors reviewed the manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Competing interests
The authors declare no competing interests.
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Fatal | ReactionOutcome | CC BY | 33707617 | 19,050,694 | 2021-03-11 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chronic lymphocytic leukaemia stage 0'. | Ustekinumab-induced chronic lymphocytic leukemia in a patient with psoriatic arthritis.
Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by skin and joint involvement. The disease may present with various joint pattern involvement, which sometimes may lead to joint destruction and deformity. Early diagnosis and treatment with disease-modifying anti-rheumatic drugs may prevent joint deformity. Recently there are many new treatment options including biologic drugs. Ustekinumab, an interleukin 12/23 inhibitor, has proven efficacy in the treatment of psoriatic arthritis. Like other biologic drugs (anti-TNF-α), there are contradictory data about the safety of ustekinumab and possible relationship with cancer development. Herein we report the development of chronic lymphocytic leukemia in a patient with PsA treated with ustekinumab.
Introduction
Psoriatic arthritis (PsA) is a chronic inflammatory disease, mainly affecting the skin and musculoskeletal system [1]. Its incidence in the general population is reported to vary between 2 and 3% [2]. Environmental and genetic factors are considered to play a role in the etiology, although it is not fully known yet.
The mechanisms that are considered to be responsible for the immunopathogenesis of the disease include the activation of T cells, particularly in the skin and joints, causing the secretion of many pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin 17 (IL-17) and interleukin 12/23 (IL-12/23). Systemic treatment with disease-modifying antirheumatic drugs (DMARDs) is required to control the clinical findings and increase the quality of life [3].
The long-term use of conventional DMARDs such as methotrexate and cyclosporine is limited due to dose-related toxicity and secondary inefficacy. Recently, a clearer understanding of the pathogenesis of PsA and inflammatory cytokine pathways supported the development of biological therapies [4]. These therapeutic agents affect various steps in the immunopathogenesis of PsA, namely by inhibiting TNF-α, IL-17 and/or the IL-12/23 pathway.
Ustekinumab is a human IgG1к monoclonal antibody that blocks the biological activity of interleukin 12 and interleukin 23 by acting on T cells, natural killer cells and receptors on antigen presenting cells [5].
Interleukin 12 and interleukin 23 are involved in the differentiation of Th1 and Th17 cells. Interleukin 12 is an inflammatory cytokine involved in both natural and adaptive immune responses and it consists of two subunits called p35 and p40 [6]. The efficacy and safety of ustekinumab in the treatment of psoriasis and psoriatic arthritis have been shown [7].
However, some immune and paradoxical reactions due to use of ustekinumab have been reported [8]. One of the major concerns of ustekinumab use is their potential of increasing the risk of cancer development. The relationship between ustekinumab and malignancy is not clear yet.
Material and methods
We analyzed studies reporting development of chronic lymphocytic leukemia due to ustekinumab use in psoriatic arthritis from PubMed and Google Scholar databases as key words using a combination of search terms such as: psoriatic arthritis, leukemia, and ustekinumab.
Using a combination of presented search terms, we undertook a systematic review of the literature for discussion and analysis of studies reporting ustekinumab related chronic lymphocytic leukemia and/or hematologic malignancy in psoriatic arthritis patients.
Case description
A 66-year-old male patient was referred to our Hematology Outpatient Clinic with complaints of fatigue, skin lesions and weight loss. According to the patient’s medical history he was followed up with PsA diagnosed until the year 2010 (Fig. 1).
Fig. 1 Psoriatic arthritis involvement and deformity of the hand joints.
The patient was treated with methotrexate (MTX) during the years 2010–2012 and thereafter with etanercept for his active psoriatic arthritis. In 2013 the etanercept was stopped because of secondary inefficacy and ustekinumab was started.
Two years later during ustekinumab treatment, the patient was admitted to the Hematology Outpatient Clinic because of complaints of fatigue, skin lesions, weight loss and abnormal findings of the blood tests.
On physical examination, skin lesions compatible with psoriasis were seen. The spleen and liver were not palpable. Auscultation revealed normal lung sounds, and a regular cardiac rhythm, with no murmurs.
Laboratory test results were as follows: erythrocyte sedimentation rate (ESR): 45 mm/h, C-reactive protein (CRP): 12 mg/dl (normal range 0–5 mg/dl), leukocyte: 13 700/µl, lymphocyte: 6700/µl, Hb: 13.5 g/dl, Htc: 39.5%, Plt: 285,000/µl. Urinalysis, liver and kidney function tests were normal, and lactate dehydrogenase (LDH) was 183 U/l (normal range 1–140 U/l).
Peripheral blood smear and bone marrow biopsy showed leukocytosis, with lymphocytes at a rate of 67%, where the majority were small and mature and some were of medium size.
Erythrocytes were normochromic normocytic and platelets were adequate in number, with normal distribution. Flow cytometric analysis was positive for CD5, CD19, CD20 and CD5+, CD19, which was consistent with stage 0 chronic lymphocytic leukemia (CLL).
Ustekinumab-related CLL was suspected and ustekinumab treatment was discontinued and low-dose corticosteroid and MTX was started for his PsA. The patient’s symptoms regressed; the fatigue and skin lesions disappeared almost totally.
Follow-up laboratory test results were as follows: ESR: 25 mm/h, CRP: 3 mg/dl (normal range 0–5 mg/dl), leukocyte: 8300/µl, lymphocyte: 4700/µl , Hb: 14.5 g/dl, Htc: 39.4%, Plt: 292,000/µl, and LDH was 122 U/l (normal range 1–140 U/l). Peripheral blood smear showed normal cell distribution. The patient’s follow-up is ongoing at the hematology and rheumatology outpatient clinics.
Results
We analyzed similar clinical problems in the literature. There have been only five case reports published in the literature regarding ustekinumab-related hematologic malignancy development. None of these cases reported the development of CLL due to ustekinumab use. Our study is the first report on this problem.
Discussion
Psoriatic arthritis is a chronic inflammatory disease characterized by skin and joint involvement. The results of observational studies and a large-scale meta-analysis revealed that patients with psoriasis and PsA carry the risk of developing malignancies, including lymphoma and skin cancer such as melanoma [9]. Whether the risk of malignancy is related to the disease itself or to immunosuppressive systemic therapy is still controversial [10].
In recent years, biologic drugs have revolutionized the treatment of PsA and made significant clinical, laboratory and radiological remission possible. Interleukin 12 and interleukin 23 are among the cytokines playing a central role in regulation of the T cell immune response and have an important role in the pathogenesis of psoriatic arthritis.
Ustekinumab is an interleukin 12/23 antagonist which has proven efficacy in the treatment of psoriatic arthritis [11].
There are few and contradictory data about the relationship between ustekinumab and hematologic malignancy development (Table I).
Table I Important reports in the literature regarding ustekinumab and hematologic malignancy
Patient diagnosis Patient age/gender Disease duration (years) Treatment drugs before ustekinumab Malignancy type Malignancy diagnosis Outcome References
Pityriasis rubra pilaris 50/female 14 years Corticosteroids Anaplastic large T-cell lymphoma Skin biopsy Good Humme et al. [13]
Crohn’s disease 29/female 8 years Azathioprine Corticosteroids Infliximab Malignant melanoma Skin biopsy Good Ehmann et al. [14]
Crohn’s disease 29/female 12 years Azathioprine Methotrexate Corticosteroids Vedolizumab Anaplastic large T-cell lymphoma Inguinal lymph node Good Smeets et al. [16]
Psoriasis 68/male 13 years Efalizumab Methotrexate MALT lymphoma Gastric biopsy Died of cerebral infarction González-Ramos et al. [17]
Psoriatic arthritis 66/male 20 years Methotrexate Etanercept CLL Bone marrow biopsy + FCA Good Current case
CLL – chronic lymphocytic leukemia, FCA – flow cytometric analysis, MALT – mucosa-associated lymphoid tissue.
Florek et al. [12] reported various adverse events of 10 years of ustekinumab use in the postmarketing period. Among these events of importance are some malignancies such as B-cell lymphoma, epithelioid sarcoma, lung and thyroid cancer. This report’s strength is that it represents real-world data, contrary to randomized controlled trials.
Thus, it should be emphasized that these strong findings indicate a possible relationship between ustekinumab and malignancy, but not causality. Also there are some reports of ustekinumab-related hematologic malignancy in various diseases.
Humme et al. [13] reported CD30-positive anaplastic large cell T-cell lymphoma under ustekinumab therapy for pityriasis rubra pilaris. The ustekinumab was stopped and the patient received CHOEP (cyclophosphamide, hydroxydaunorubicin, oncovin, etoposide, prednisone) chemotherapy.
Ehmann et al. [14] reported malignant melanoma during ustekinumab therapy of Crohn’s disease. Scherl et al. [15] reported some cases of malignancies of the prostate, thyroid and colon, while hematologic malignancy was not seen. Smeets et al. [16] reported anaplastic large T-cell lymphoma in a patient with Crohn’s disease during ustekinumab treatment. Treatment with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) was initiated. Unfortunately, the patient had a refractory lymphoma and proceeded to allogenic stem cell transplantation.
González-Ramos et al. [17] presented gastric mucosa-associated lymphoid tissue lymphoma in a patient with severe psoriasis receiving ustekinumab. The described patient received 19 sessions of radiation therapy, which resulted in complete remission of the disease. Chronic lymphocytic leukemia, as diagnosed in the presented case, has not been observed so far.
Other studies found no significant relationship between ustekinumab and the risk of malignancy [18]. The contradictory results reported in the studies are explained with various reasons: patient selection, type and duration of disease, family history of malignancy and use of another immunosuppressive drugs.
It should be noted that a limitation of the analysis is still the relatively short time of using ustekinumab in the treatment of psoriatic arthritis.
Conclusions
This presentation reports occurrence of CLL in a patient with PsA treated with ustekinumab which may point to plausible time relation with use of this drug. However, this is only “possible” but not “certain” causality.
So, far there have been no unequivocal associations of ustekinumab with the development of malignancy in the available literature. At present, many studies and observations are inconsistent and the study groups are incomparable with each other.
In this subject further observations in real life studies and in the longer period of time are needed.
The authors declare no conflict of interest. | USTEKINUMAB | DrugsGivenReaction | CC BY-NC-SA | 33707797 | 19,006,216 | 2021 |
What was the administration route of drug 'USTEKINUMAB'? | Ustekinumab-induced chronic lymphocytic leukemia in a patient with psoriatic arthritis.
Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by skin and joint involvement. The disease may present with various joint pattern involvement, which sometimes may lead to joint destruction and deformity. Early diagnosis and treatment with disease-modifying anti-rheumatic drugs may prevent joint deformity. Recently there are many new treatment options including biologic drugs. Ustekinumab, an interleukin 12/23 inhibitor, has proven efficacy in the treatment of psoriatic arthritis. Like other biologic drugs (anti-TNF-α), there are contradictory data about the safety of ustekinumab and possible relationship with cancer development. Herein we report the development of chronic lymphocytic leukemia in a patient with PsA treated with ustekinumab.
Introduction
Psoriatic arthritis (PsA) is a chronic inflammatory disease, mainly affecting the skin and musculoskeletal system [1]. Its incidence in the general population is reported to vary between 2 and 3% [2]. Environmental and genetic factors are considered to play a role in the etiology, although it is not fully known yet.
The mechanisms that are considered to be responsible for the immunopathogenesis of the disease include the activation of T cells, particularly in the skin and joints, causing the secretion of many pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin 17 (IL-17) and interleukin 12/23 (IL-12/23). Systemic treatment with disease-modifying antirheumatic drugs (DMARDs) is required to control the clinical findings and increase the quality of life [3].
The long-term use of conventional DMARDs such as methotrexate and cyclosporine is limited due to dose-related toxicity and secondary inefficacy. Recently, a clearer understanding of the pathogenesis of PsA and inflammatory cytokine pathways supported the development of biological therapies [4]. These therapeutic agents affect various steps in the immunopathogenesis of PsA, namely by inhibiting TNF-α, IL-17 and/or the IL-12/23 pathway.
Ustekinumab is a human IgG1к monoclonal antibody that blocks the biological activity of interleukin 12 and interleukin 23 by acting on T cells, natural killer cells and receptors on antigen presenting cells [5].
Interleukin 12 and interleukin 23 are involved in the differentiation of Th1 and Th17 cells. Interleukin 12 is an inflammatory cytokine involved in both natural and adaptive immune responses and it consists of two subunits called p35 and p40 [6]. The efficacy and safety of ustekinumab in the treatment of psoriasis and psoriatic arthritis have been shown [7].
However, some immune and paradoxical reactions due to use of ustekinumab have been reported [8]. One of the major concerns of ustekinumab use is their potential of increasing the risk of cancer development. The relationship between ustekinumab and malignancy is not clear yet.
Material and methods
We analyzed studies reporting development of chronic lymphocytic leukemia due to ustekinumab use in psoriatic arthritis from PubMed and Google Scholar databases as key words using a combination of search terms such as: psoriatic arthritis, leukemia, and ustekinumab.
Using a combination of presented search terms, we undertook a systematic review of the literature for discussion and analysis of studies reporting ustekinumab related chronic lymphocytic leukemia and/or hematologic malignancy in psoriatic arthritis patients.
Case description
A 66-year-old male patient was referred to our Hematology Outpatient Clinic with complaints of fatigue, skin lesions and weight loss. According to the patient’s medical history he was followed up with PsA diagnosed until the year 2010 (Fig. 1).
Fig. 1 Psoriatic arthritis involvement and deformity of the hand joints.
The patient was treated with methotrexate (MTX) during the years 2010–2012 and thereafter with etanercept for his active psoriatic arthritis. In 2013 the etanercept was stopped because of secondary inefficacy and ustekinumab was started.
Two years later during ustekinumab treatment, the patient was admitted to the Hematology Outpatient Clinic because of complaints of fatigue, skin lesions, weight loss and abnormal findings of the blood tests.
On physical examination, skin lesions compatible with psoriasis were seen. The spleen and liver were not palpable. Auscultation revealed normal lung sounds, and a regular cardiac rhythm, with no murmurs.
Laboratory test results were as follows: erythrocyte sedimentation rate (ESR): 45 mm/h, C-reactive protein (CRP): 12 mg/dl (normal range 0–5 mg/dl), leukocyte: 13 700/µl, lymphocyte: 6700/µl, Hb: 13.5 g/dl, Htc: 39.5%, Plt: 285,000/µl. Urinalysis, liver and kidney function tests were normal, and lactate dehydrogenase (LDH) was 183 U/l (normal range 1–140 U/l).
Peripheral blood smear and bone marrow biopsy showed leukocytosis, with lymphocytes at a rate of 67%, where the majority were small and mature and some were of medium size.
Erythrocytes were normochromic normocytic and platelets were adequate in number, with normal distribution. Flow cytometric analysis was positive for CD5, CD19, CD20 and CD5+, CD19, which was consistent with stage 0 chronic lymphocytic leukemia (CLL).
Ustekinumab-related CLL was suspected and ustekinumab treatment was discontinued and low-dose corticosteroid and MTX was started for his PsA. The patient’s symptoms regressed; the fatigue and skin lesions disappeared almost totally.
Follow-up laboratory test results were as follows: ESR: 25 mm/h, CRP: 3 mg/dl (normal range 0–5 mg/dl), leukocyte: 8300/µl, lymphocyte: 4700/µl , Hb: 14.5 g/dl, Htc: 39.4%, Plt: 292,000/µl, and LDH was 122 U/l (normal range 1–140 U/l). Peripheral blood smear showed normal cell distribution. The patient’s follow-up is ongoing at the hematology and rheumatology outpatient clinics.
Results
We analyzed similar clinical problems in the literature. There have been only five case reports published in the literature regarding ustekinumab-related hematologic malignancy development. None of these cases reported the development of CLL due to ustekinumab use. Our study is the first report on this problem.
Discussion
Psoriatic arthritis is a chronic inflammatory disease characterized by skin and joint involvement. The results of observational studies and a large-scale meta-analysis revealed that patients with psoriasis and PsA carry the risk of developing malignancies, including lymphoma and skin cancer such as melanoma [9]. Whether the risk of malignancy is related to the disease itself or to immunosuppressive systemic therapy is still controversial [10].
In recent years, biologic drugs have revolutionized the treatment of PsA and made significant clinical, laboratory and radiological remission possible. Interleukin 12 and interleukin 23 are among the cytokines playing a central role in regulation of the T cell immune response and have an important role in the pathogenesis of psoriatic arthritis.
Ustekinumab is an interleukin 12/23 antagonist which has proven efficacy in the treatment of psoriatic arthritis [11].
There are few and contradictory data about the relationship between ustekinumab and hematologic malignancy development (Table I).
Table I Important reports in the literature regarding ustekinumab and hematologic malignancy
Patient diagnosis Patient age/gender Disease duration (years) Treatment drugs before ustekinumab Malignancy type Malignancy diagnosis Outcome References
Pityriasis rubra pilaris 50/female 14 years Corticosteroids Anaplastic large T-cell lymphoma Skin biopsy Good Humme et al. [13]
Crohn’s disease 29/female 8 years Azathioprine Corticosteroids Infliximab Malignant melanoma Skin biopsy Good Ehmann et al. [14]
Crohn’s disease 29/female 12 years Azathioprine Methotrexate Corticosteroids Vedolizumab Anaplastic large T-cell lymphoma Inguinal lymph node Good Smeets et al. [16]
Psoriasis 68/male 13 years Efalizumab Methotrexate MALT lymphoma Gastric biopsy Died of cerebral infarction González-Ramos et al. [17]
Psoriatic arthritis 66/male 20 years Methotrexate Etanercept CLL Bone marrow biopsy + FCA Good Current case
CLL – chronic lymphocytic leukemia, FCA – flow cytometric analysis, MALT – mucosa-associated lymphoid tissue.
Florek et al. [12] reported various adverse events of 10 years of ustekinumab use in the postmarketing period. Among these events of importance are some malignancies such as B-cell lymphoma, epithelioid sarcoma, lung and thyroid cancer. This report’s strength is that it represents real-world data, contrary to randomized controlled trials.
Thus, it should be emphasized that these strong findings indicate a possible relationship between ustekinumab and malignancy, but not causality. Also there are some reports of ustekinumab-related hematologic malignancy in various diseases.
Humme et al. [13] reported CD30-positive anaplastic large cell T-cell lymphoma under ustekinumab therapy for pityriasis rubra pilaris. The ustekinumab was stopped and the patient received CHOEP (cyclophosphamide, hydroxydaunorubicin, oncovin, etoposide, prednisone) chemotherapy.
Ehmann et al. [14] reported malignant melanoma during ustekinumab therapy of Crohn’s disease. Scherl et al. [15] reported some cases of malignancies of the prostate, thyroid and colon, while hematologic malignancy was not seen. Smeets et al. [16] reported anaplastic large T-cell lymphoma in a patient with Crohn’s disease during ustekinumab treatment. Treatment with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) was initiated. Unfortunately, the patient had a refractory lymphoma and proceeded to allogenic stem cell transplantation.
González-Ramos et al. [17] presented gastric mucosa-associated lymphoid tissue lymphoma in a patient with severe psoriasis receiving ustekinumab. The described patient received 19 sessions of radiation therapy, which resulted in complete remission of the disease. Chronic lymphocytic leukemia, as diagnosed in the presented case, has not been observed so far.
Other studies found no significant relationship between ustekinumab and the risk of malignancy [18]. The contradictory results reported in the studies are explained with various reasons: patient selection, type and duration of disease, family history of malignancy and use of another immunosuppressive drugs.
It should be noted that a limitation of the analysis is still the relatively short time of using ustekinumab in the treatment of psoriatic arthritis.
Conclusions
This presentation reports occurrence of CLL in a patient with PsA treated with ustekinumab which may point to plausible time relation with use of this drug. However, this is only “possible” but not “certain” causality.
So, far there have been no unequivocal associations of ustekinumab with the development of malignancy in the available literature. At present, many studies and observations are inconsistent and the study groups are incomparable with each other.
In this subject further observations in real life studies and in the longer period of time are needed.
The authors declare no conflict of interest. | Subcutaneous | DrugAdministrationRoute | CC BY-NC-SA | 33707797 | 19,006,216 | 2021 |
What was the outcome of reaction 'Chronic lymphocytic leukaemia stage 0'? | Ustekinumab-induced chronic lymphocytic leukemia in a patient with psoriatic arthritis.
Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by skin and joint involvement. The disease may present with various joint pattern involvement, which sometimes may lead to joint destruction and deformity. Early diagnosis and treatment with disease-modifying anti-rheumatic drugs may prevent joint deformity. Recently there are many new treatment options including biologic drugs. Ustekinumab, an interleukin 12/23 inhibitor, has proven efficacy in the treatment of psoriatic arthritis. Like other biologic drugs (anti-TNF-α), there are contradictory data about the safety of ustekinumab and possible relationship with cancer development. Herein we report the development of chronic lymphocytic leukemia in a patient with PsA treated with ustekinumab.
Introduction
Psoriatic arthritis (PsA) is a chronic inflammatory disease, mainly affecting the skin and musculoskeletal system [1]. Its incidence in the general population is reported to vary between 2 and 3% [2]. Environmental and genetic factors are considered to play a role in the etiology, although it is not fully known yet.
The mechanisms that are considered to be responsible for the immunopathogenesis of the disease include the activation of T cells, particularly in the skin and joints, causing the secretion of many pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin 17 (IL-17) and interleukin 12/23 (IL-12/23). Systemic treatment with disease-modifying antirheumatic drugs (DMARDs) is required to control the clinical findings and increase the quality of life [3].
The long-term use of conventional DMARDs such as methotrexate and cyclosporine is limited due to dose-related toxicity and secondary inefficacy. Recently, a clearer understanding of the pathogenesis of PsA and inflammatory cytokine pathways supported the development of biological therapies [4]. These therapeutic agents affect various steps in the immunopathogenesis of PsA, namely by inhibiting TNF-α, IL-17 and/or the IL-12/23 pathway.
Ustekinumab is a human IgG1к monoclonal antibody that blocks the biological activity of interleukin 12 and interleukin 23 by acting on T cells, natural killer cells and receptors on antigen presenting cells [5].
Interleukin 12 and interleukin 23 are involved in the differentiation of Th1 and Th17 cells. Interleukin 12 is an inflammatory cytokine involved in both natural and adaptive immune responses and it consists of two subunits called p35 and p40 [6]. The efficacy and safety of ustekinumab in the treatment of psoriasis and psoriatic arthritis have been shown [7].
However, some immune and paradoxical reactions due to use of ustekinumab have been reported [8]. One of the major concerns of ustekinumab use is their potential of increasing the risk of cancer development. The relationship between ustekinumab and malignancy is not clear yet.
Material and methods
We analyzed studies reporting development of chronic lymphocytic leukemia due to ustekinumab use in psoriatic arthritis from PubMed and Google Scholar databases as key words using a combination of search terms such as: psoriatic arthritis, leukemia, and ustekinumab.
Using a combination of presented search terms, we undertook a systematic review of the literature for discussion and analysis of studies reporting ustekinumab related chronic lymphocytic leukemia and/or hematologic malignancy in psoriatic arthritis patients.
Case description
A 66-year-old male patient was referred to our Hematology Outpatient Clinic with complaints of fatigue, skin lesions and weight loss. According to the patient’s medical history he was followed up with PsA diagnosed until the year 2010 (Fig. 1).
Fig. 1 Psoriatic arthritis involvement and deformity of the hand joints.
The patient was treated with methotrexate (MTX) during the years 2010–2012 and thereafter with etanercept for his active psoriatic arthritis. In 2013 the etanercept was stopped because of secondary inefficacy and ustekinumab was started.
Two years later during ustekinumab treatment, the patient was admitted to the Hematology Outpatient Clinic because of complaints of fatigue, skin lesions, weight loss and abnormal findings of the blood tests.
On physical examination, skin lesions compatible with psoriasis were seen. The spleen and liver were not palpable. Auscultation revealed normal lung sounds, and a regular cardiac rhythm, with no murmurs.
Laboratory test results were as follows: erythrocyte sedimentation rate (ESR): 45 mm/h, C-reactive protein (CRP): 12 mg/dl (normal range 0–5 mg/dl), leukocyte: 13 700/µl, lymphocyte: 6700/µl, Hb: 13.5 g/dl, Htc: 39.5%, Plt: 285,000/µl. Urinalysis, liver and kidney function tests were normal, and lactate dehydrogenase (LDH) was 183 U/l (normal range 1–140 U/l).
Peripheral blood smear and bone marrow biopsy showed leukocytosis, with lymphocytes at a rate of 67%, where the majority were small and mature and some were of medium size.
Erythrocytes were normochromic normocytic and platelets were adequate in number, with normal distribution. Flow cytometric analysis was positive for CD5, CD19, CD20 and CD5+, CD19, which was consistent with stage 0 chronic lymphocytic leukemia (CLL).
Ustekinumab-related CLL was suspected and ustekinumab treatment was discontinued and low-dose corticosteroid and MTX was started for his PsA. The patient’s symptoms regressed; the fatigue and skin lesions disappeared almost totally.
Follow-up laboratory test results were as follows: ESR: 25 mm/h, CRP: 3 mg/dl (normal range 0–5 mg/dl), leukocyte: 8300/µl, lymphocyte: 4700/µl , Hb: 14.5 g/dl, Htc: 39.4%, Plt: 292,000/µl, and LDH was 122 U/l (normal range 1–140 U/l). Peripheral blood smear showed normal cell distribution. The patient’s follow-up is ongoing at the hematology and rheumatology outpatient clinics.
Results
We analyzed similar clinical problems in the literature. There have been only five case reports published in the literature regarding ustekinumab-related hematologic malignancy development. None of these cases reported the development of CLL due to ustekinumab use. Our study is the first report on this problem.
Discussion
Psoriatic arthritis is a chronic inflammatory disease characterized by skin and joint involvement. The results of observational studies and a large-scale meta-analysis revealed that patients with psoriasis and PsA carry the risk of developing malignancies, including lymphoma and skin cancer such as melanoma [9]. Whether the risk of malignancy is related to the disease itself or to immunosuppressive systemic therapy is still controversial [10].
In recent years, biologic drugs have revolutionized the treatment of PsA and made significant clinical, laboratory and radiological remission possible. Interleukin 12 and interleukin 23 are among the cytokines playing a central role in regulation of the T cell immune response and have an important role in the pathogenesis of psoriatic arthritis.
Ustekinumab is an interleukin 12/23 antagonist which has proven efficacy in the treatment of psoriatic arthritis [11].
There are few and contradictory data about the relationship between ustekinumab and hematologic malignancy development (Table I).
Table I Important reports in the literature regarding ustekinumab and hematologic malignancy
Patient diagnosis Patient age/gender Disease duration (years) Treatment drugs before ustekinumab Malignancy type Malignancy diagnosis Outcome References
Pityriasis rubra pilaris 50/female 14 years Corticosteroids Anaplastic large T-cell lymphoma Skin biopsy Good Humme et al. [13]
Crohn’s disease 29/female 8 years Azathioprine Corticosteroids Infliximab Malignant melanoma Skin biopsy Good Ehmann et al. [14]
Crohn’s disease 29/female 12 years Azathioprine Methotrexate Corticosteroids Vedolizumab Anaplastic large T-cell lymphoma Inguinal lymph node Good Smeets et al. [16]
Psoriasis 68/male 13 years Efalizumab Methotrexate MALT lymphoma Gastric biopsy Died of cerebral infarction González-Ramos et al. [17]
Psoriatic arthritis 66/male 20 years Methotrexate Etanercept CLL Bone marrow biopsy + FCA Good Current case
CLL – chronic lymphocytic leukemia, FCA – flow cytometric analysis, MALT – mucosa-associated lymphoid tissue.
Florek et al. [12] reported various adverse events of 10 years of ustekinumab use in the postmarketing period. Among these events of importance are some malignancies such as B-cell lymphoma, epithelioid sarcoma, lung and thyroid cancer. This report’s strength is that it represents real-world data, contrary to randomized controlled trials.
Thus, it should be emphasized that these strong findings indicate a possible relationship between ustekinumab and malignancy, but not causality. Also there are some reports of ustekinumab-related hematologic malignancy in various diseases.
Humme et al. [13] reported CD30-positive anaplastic large cell T-cell lymphoma under ustekinumab therapy for pityriasis rubra pilaris. The ustekinumab was stopped and the patient received CHOEP (cyclophosphamide, hydroxydaunorubicin, oncovin, etoposide, prednisone) chemotherapy.
Ehmann et al. [14] reported malignant melanoma during ustekinumab therapy of Crohn’s disease. Scherl et al. [15] reported some cases of malignancies of the prostate, thyroid and colon, while hematologic malignancy was not seen. Smeets et al. [16] reported anaplastic large T-cell lymphoma in a patient with Crohn’s disease during ustekinumab treatment. Treatment with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) was initiated. Unfortunately, the patient had a refractory lymphoma and proceeded to allogenic stem cell transplantation.
González-Ramos et al. [17] presented gastric mucosa-associated lymphoid tissue lymphoma in a patient with severe psoriasis receiving ustekinumab. The described patient received 19 sessions of radiation therapy, which resulted in complete remission of the disease. Chronic lymphocytic leukemia, as diagnosed in the presented case, has not been observed so far.
Other studies found no significant relationship between ustekinumab and the risk of malignancy [18]. The contradictory results reported in the studies are explained with various reasons: patient selection, type and duration of disease, family history of malignancy and use of another immunosuppressive drugs.
It should be noted that a limitation of the analysis is still the relatively short time of using ustekinumab in the treatment of psoriatic arthritis.
Conclusions
This presentation reports occurrence of CLL in a patient with PsA treated with ustekinumab which may point to plausible time relation with use of this drug. However, this is only “possible” but not “certain” causality.
So, far there have been no unequivocal associations of ustekinumab with the development of malignancy in the available literature. At present, many studies and observations are inconsistent and the study groups are incomparable with each other.
In this subject further observations in real life studies and in the longer period of time are needed.
The authors declare no conflict of interest. | Recovering | ReactionOutcome | CC BY-NC-SA | 33707797 | 19,006,216 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Intractable Biliary Candidiasis in Patients with Obstructive Jaundice and Regional Malignancy: A Retrospective Case Series.
Candida species are infrequently grown in bile cultures. An association between biliary candidiasis and regional malignancy may exist. The role of fungus membranes in frequent biliary stent occlusion is also presented in this case series.
We retrospectively identified patients who underwent percutaneous trans-hepatic cholangiogram (PTC) for obstructive jaundice between January 2014 and January 2019. The results of bile cultures - obtained by PTC - for all patients were analyzed, and patients with fungus growth were determined; their medical records were reviewed.
A total of 71 patients with obstructive jaundice underwent PTC between January 2015 and January 2019. Five patients (all male; mean age 55.8 years) had candida species growth in bile cultures. Two patients were diagnosed with cholangiocarcinoma, one with adenocarcinoma of the head of the pancreas, one with gallbladder cancer, and one with locally advanced gastric adenocarcinoma. Formation of fungal balls predisposed to frequent PTC drain clogging. Eradication of Candida was achieved in 4 patients after 10 days to 3 weeks of antifungal therapy.
We present a case series of biliary candidiasis in patients with obstructive jaundice and regional malignancy. We suggest that patients with obstructive jaundice and regional malignancy should be screened for biliary candidiasis. Persistent cholestasis may be caused by the recurrent formation of fungal membranes (balls).
Introduction
Fungi represent an important cause of infection to human being. Candida albicans is the most pathogenic yeast species.1 Candida parapsilosis, Candida glabrata, Candida tropicalis and the newly identified (1995) species of Candida dubliniensis (Dublin, Ireland)2 have also been associated with most forms of candidiasis. Fungal infections are frequently recognized, especially in patients with risk factors including cystic fibrosis, long term antibiotic therapy, prolonged critical care admission, and immunosuppression.3 Fungal involvement of the biliary tract seems to occur more often nowadays, probably due to the greater use of biliary interventions, both endoscopic and percutaneous.4 Data concerning the microbiological flora of the biliary tract are scarce, probably due to methodological limitations.4 Although bile analysis is useful to guide the therapeutic procedures in patients with biliary infections, few studies performed a microbiological analysis of bile in patients with different biliary diseases (Figure 1).Figure 1 Light microscopy for histopathology smears of infected bile (400×), (A) budding yeast (B) Candida albicans demonstrating chlamydospores (arrow 1), blastospores (arrow 2) and pseudohyphae (arrow 3).
Table 1 Clinical Course, Management and Outcome of Patients
Patient No.1 Patient No.2 Patient No.3 Patient No.4 Patient No.5
Fungus species Candida albicans Candida glabrata Candida albicans Candida albicans Candida albicans
Antifungal treatment Fluconazole “systemic” 200mg/day
Twice -daily drain flush with 100mg fluconazole Fluconazole,systemic 200mg/day
Twice -daily drain flush with 100mg fluconazole Fluconazole,systemic 200mg/day
Systemic Caspofungin
Twice -daily drain flush with 100mg fluconazole Systemic,Fluconazole Fluconazole “systemic” 200mg/day
Twice -daily drain flush with 100mg fluconazole
Fungal eradication Yes, after 10 days Yes, after 2 months No eradication after 6 months. Yes, after 2 weeks Yes after 5 weeks
Interventions - ERCP* attempted and failed.
-PTC**: internal external drainage
- PTC: metallic stent with external drainage.
-PTC: removal of drainage. - ERCP: failed and complicated by duodenal perforation.
- PTC: internal external drainage for persistent jaundice.
- PTC: metallic stent deployed, drainage kept in place.
- Whipple’s surgery
- PTC: stent with external drainage due to postoperative bile leak and anastomotic stricture.
- PTC: stent removed - ERCP: insertion of rubber stent at another hospital before presenting to us.
- PTC: internal external drainage.
- multiple PTC procedures for replacement and repositioning of drains. -ERCP attempted and failed.
-PTC: internal external drainage.
- PTC: metallic stent deployed, drain removed. -ERCP failed.
-PTC: internal external drainage.
- multiple PTC procedures for replacement and repositioning of drains.
- PTC: metallic stent deployed, drain removed.
Following interventions Chemotherapy Chemotherapy None Chemotherapy Chemotherapy
Survival after presentation Alive after 5 months Death after 15 months Death after 6 months Death after 6 months Death after 7 months
Abbreviations: *ERCP, endoscopic retrograde cholangiopancreatography; **PTC, percutaneous transhepatic cholangiogram.
Table 2 Clinical and Demographic Features of Patients
Patient No. Age Gender Clinical Presentation Primary Diagnosis Disease Stage (Radiologic) Comorbidities
1 71 Male Obstructive jaundice Gallbladder Cancer Extensive distant lymph node involvement and mesenteric deposits Previous History of urinary bladder Cancer
2 51 Male Obstructive jaundice Adenocarcinoma of the head of the pancreas No evidence of metastasis Stage 1b Smoker, FAP mutation with history of colectomy
3 54 Male Obstructive jaundice, abdominal pain Distal cholangiocarcinoma Pleural and lungs metastasis Diabetes Mellitus
4 40 Male Obstructive jaundice, epigastric pain Advanced gastric cancer Liver metastasis and extensive Lymph node involvement Smoker
5 63 Male Obstructive jaundice, epigastric pain Adenocarcinoma of the head of the pancreas Multiple liver metastatic lesions Hypertension
Abbreviation: FAP, familial adenomatous polyposis.
Despite the emerging awareness of biliary candidiasis, its clinical relevance and potential risk factors remain debatable The terms “Biliary candidiasis” or “Biliary mycosis” are alternatively used when candida species is detected in microbiological bile fluid analysis, with or without cholangitis. However, it is still controversial whether positive bile analysis represents fungal infection or colonization, and how the results should impact the therapeutic approach. In this study, we review cases of biliary candidiasis in the setting of biliary or regional malignancy, highlighting the potential correlation between biliary candidiasis and malignancy. Additionally, we describe the role of fungus balls in frequent biliary stent occlusion.
Patients and Methods
Study Design
This is a retrospective study in which we identified patients who underwent percutaneous trans-hepatic cholangiogram (PTC) for obstructive jaundice between January 2015 and January 2019. The results of bile cultures for all patients were examined.
Inclusion Criteria
Only patients with fungus growth in bile cultures were included. The medical records of these patients were reviewed, and definitive diagnosis, management protocols, and outcomes were described.
Ethics
The study protocol was reviewed and approved by the Institutional Review Board at King Abdullah University Hospital and by the Committee of Research on Human Subjects at the Jordan University of Science and Technology. (Non-funded research No: 20200438). We protected Patients’ confidentiality in accordance with declaration of Helsinki provisions. Written informed consent was obtained from the patients for the inclusion of their clinical data within this work.
Procedures
Endoscopic retrograde cholangiopancreatography (ERCP), as the intervention of choice, was attempted by an experienced gastroenterologist in those 5 patients. Inability to achieve biliary access in those patients through ERCP was attributed to the high-grade blockage of the distal portion of the common bile duct.5
Therefore, PTC was performed next, in which the level of obstruction was demonstrated, bypassed, and balloon-dilated. Bile samples for cultures for bacteria and fungi were obtained, and biopsies and/or brush cytology were taken. Occasionally, Candida pseudohyphae were directly observed on bile smears. We submitted samples for fungal culture in patients with a high-grade obstruction or prolonged jaundice. The specimens were cultivated both on Kimmig agar plates and in Sabouraud bouillons and additional delineation was performed by micromorphological and biochemical methods.
During initial PTC, internal plastic stents were placed without the routine use of external drainage, given that distal contrast runoff was smooth and free. After stent placement, an initial drop in cholestatic indices (direct bilirubin, alkaline phosphatase, gamma-GT) level was observed in nearly all patients, but then it spiked again in 48 to 72hrs. A repeat PTC confirmed partial or complete blockage of the stent with filling defects (fungus balls) in the common bile duct (Figure 2). Therefore, bile samples were resubmitted and an internal-external biliary drain was left in place. The daily drainage through the external catheter ranged from one to two liters, indicating persistent or recurrent occlusion. Multiple PTC stent revisions were necessary for several patients as shown in Table 1.Figure 2 Common bile duct stent partial occlusion with filling defects (fungus balls) at the tip of the black arrow.
Following the diagnosis of fungal cholangitis with direct visualization of pseudohyphae in smears or positive culture growth, we started systemic antifungals with fluconazole 200mg/day and twice-daily drain flush with 100mg of fluconazole until repeat culture showed no growth.
Results
A total of 71 patients (mean age: 55.8, M: F 5:0) with obstructive jaundice underwent PTC between January 2015 and January 2019. Only 5 patients (7%) had candida growth on PTC-obtained bile cultures (4 Candida albicans, 1 Candida glabrata). Two patients were diagnosed with cholangiocarcinoma, one with adenocarcinoma of the head of the pancreas, one with gallbladder cancer, and one with gastric adenocarcinoma. The patient with pancreatic adenocarcinoma experienced fungal cholangitis, which was successfully eradicated, and then he underwent a pancreaticoduodenectomy (Whipple’s procedure). The rest of the patients had metastatic disease at the time of diagnosis and were referred -after fungus eradication- for chemotherapy. Table 2 summarizes the clinical and demographic features of our cases. Patients’ comorbidities, disease staging, treatment options, and outcomes are illustrated in Table 1. Formation of fungal membranes predisposed to frequent drain clogging. Eradication was achieved in 4 patients after 10 days, 2 months, 2 weeks, and 3 weeks. One patient died after 6 months with persistent candida growth and frequent stent occlusion. Concerning the other 4 patients, chemotherapy delay intervals correlated with the aforementioned eradication periods.
Discussion
In this series, although we cultured candida species in 7% of patients undergoing PTC, we demonstrated that all patients with biliary candidiasis are found to have biliary or regional malignancy. In spite of the fact that other predisposing factors –including immunodeficiency, biliary instrumentation, and prolonged stagnation due to stricture- contribute to fungus overgrowth inside bile ducts, this rare infection was alarming for the presence of cancer.
Fungal cholangitis, as a form of Invasive candidiasis, is a leading cause of sepsis (candidemia) in this population, ie; patients with locoregional malignancies. Given the high cost of antifungal drugs, the potential for toxicity with prolonged use, and the poorer outcomes associated with delayed therapy; it is highly recommended that clinical microbiology as well as infectious diseases services are incorporated in the diagnosis and management of invasive candidiasis. The guidelines published by National Institute for Health and Care Excellence (NICE)6 along with 2019 updates on the core elements of hospital antibiotic Stewardship programs, both emphasized the importance of tracking, monitoring, and reporting of antimicrobial impact and outcomes.7
Welch has first described microbial presence in bile more than 130 years ago when Bacteria implication in gallstone pathogenesis was revealed.8,9 Pathogens may enter the biliary tree by a retrograde ascent from the duodenum -where 100–1000 bacteria live in each 1 milliliter of its’ lining mucosa- or from portal venous blood or during instrumentation of CBD.10
Because of the existence of biliary sphincter, bile flow, and some bile components that have antibacterial features, such as bile acids and immunoglobulin A (IgA), many authors suggest that bile in the biliary tract would be normally sterile unless the bile ducts are obstructed, or stones are present.11 On the contrary, multiple bacterial strains that can grow in bile (bile-tolerant) have been recently identified with the application of next-generation sequencing.12 These strains may induce chronic infection with possible malignant transformation (eg Helicobacter species, Hemophilus influenzae, E. coli).13
Moreover, in a study of 19 bile samples obtained during surgery from patients with a normal biliary tree (no stones or obstruction), there was positive growth in 16/19 samples for bacteria which led to a conclusion that human bile is not, as first thought, sterile.14
Most studies were conducted on abnormal biliary systems or unhealthy individuals. To make more reliable conclusions on the normal flora of the biliary system we believe that further studies of the normal biliary system of healthy individuals are warranted. However, this type of study may face technical challenges or ethical barriers. Therefore, we recommend obtaining bile cultures in all cases of biliary obstruction, and we believe that fungus growth in bile cultures obtained by PTC is of clinical significance.
In patients with obstructive jaundice, ERCP is usually attempted first. According to the American Society for Gastrointestinal Endoscopy (ASGE) guidelines,15 ERCP is the intervention of choice due to its advantage of drainage without the need for an external catheter. However, ERCP has a failure rate of 10–15%.16 Common reported causes of ERCP failure include duodenal diverticula, which increases with age, adhesions due to previous upper abdominal surgery or gastrointestinal diversions, or to a less extent obstruction due to tumors.17 The failure rate increases by 78-fold in patients with periampullary tumors that infiltrate the ampulla of Vater. Hence, PTC is a suitable alternative, especially in patients with a hilar obstruction or surgically-altered anatomy.18
Since bile samples from PTC are less prone to contamination by intestinal flora than ERCP samples, cultures from PTC samples are more reliable for an accurate diagnosis and antimicrobial selection.19
Several studies10,20,21 have investigated biliary candidiasis in terms of clinical presentation, diagnosis, and treatment modalities. However, only a few studies have analyzed its correlation with malignancy22 and the impact on patient outcomes, including survival rates. In a study by Kim and colleagues,18 Candida species were found in 23% of bile samples collected during PTC from patients with cholangiocarcinoma; Patients with biliary candidiasis had reduced survival compared to those without, the authors suggested that biliary candidiasis is a factor of poor prognosis. Reduced survival is probably attributed to factors such as sepsis, poor oral intake, complications of frequent invasive interventions, and delayed surgery or chemotherapy.
In another study by Lenz and colleagues,4 in which bile samples were collected during ERCP, Candida was isolated in 30% of patients. However, all patients suffered from severe chronic diseases and required frequent intervention; the authors found in a multivariate analysis that previous endoscopic sphincterotomy -which eliminates an important protective mechanism- was a significant risk factor for biliary candidiasis.
Other studies have demonstrated that fungus balls could be responsible for frequent CBD and stent occlusion. Story and Gluck23 described the soft filling defects within the bile duct. They also outlined the treatment approach, which consisted of daily oral antifungal and daily antifungal flushing through PTC external drain or cholecystostomy tube. In that study, the proposed treatment succeeded in the eradication of the infection in about 75% of cases.
In the present study, the diagnosis of fungal cholangitis preceded that of malignancy, suggesting that biliary candidiasis could be a warning sign of an underlying malignancy. We also highlight the role of fungus balls in frequent stent occlusion after PTC or ERCP, which is a rare but potentially treatable condition. Additionally, we emphasize the role of combined (systemic and intra-biliary) antifungal therapy in eradicating the pathogen. Our results suggest that biliary candidiasis could be associated with a worse prognosis.
This study has some limitations. Firstly, it is a retrospective study. Secondly, the sample size of patients with biliary candidiasis was too small to evaluate risk factors with statistical significance. Thirdly, many patients who did not have their bile cultures obtained may still have the infection, leading to some false-negative cases. Despite these limitations, the findings in this study contribute to the understanding of cancer association with biliary candidiasis and the importance of the implementation of an appropriate treatment approach.
In Conclusion, sampling bile for culture is recommended in patients with obstructive jaundice. Biliary candidiasis should raise concerns of underlying biliary or regional malignancy, in particular in the absence of other risk factors. Persistent cholestasis after biliary drainage may be attributed to fungus growth in the form of fungal balls, which may delay treatment by chemotherapy or surgery. Future prospective studies are warranted to investigate the putative association between biliary candidiasis and malignancy.
Disclosure
The authors report no conflicts of interest for this work. | CASPOFUNGIN ACETATE, FLUCONAZOLE | DrugsGivenReaction | CC BY-NC | 33707962 | 19,814,211 | 2021 |
What was the outcome of reaction 'Drug ineffective'? | Intractable Biliary Candidiasis in Patients with Obstructive Jaundice and Regional Malignancy: A Retrospective Case Series.
Candida species are infrequently grown in bile cultures. An association between biliary candidiasis and regional malignancy may exist. The role of fungus membranes in frequent biliary stent occlusion is also presented in this case series.
We retrospectively identified patients who underwent percutaneous trans-hepatic cholangiogram (PTC) for obstructive jaundice between January 2014 and January 2019. The results of bile cultures - obtained by PTC - for all patients were analyzed, and patients with fungus growth were determined; their medical records were reviewed.
A total of 71 patients with obstructive jaundice underwent PTC between January 2015 and January 2019. Five patients (all male; mean age 55.8 years) had candida species growth in bile cultures. Two patients were diagnosed with cholangiocarcinoma, one with adenocarcinoma of the head of the pancreas, one with gallbladder cancer, and one with locally advanced gastric adenocarcinoma. Formation of fungal balls predisposed to frequent PTC drain clogging. Eradication of Candida was achieved in 4 patients after 10 days to 3 weeks of antifungal therapy.
We present a case series of biliary candidiasis in patients with obstructive jaundice and regional malignancy. We suggest that patients with obstructive jaundice and regional malignancy should be screened for biliary candidiasis. Persistent cholestasis may be caused by the recurrent formation of fungal membranes (balls).
Introduction
Fungi represent an important cause of infection to human being. Candida albicans is the most pathogenic yeast species.1 Candida parapsilosis, Candida glabrata, Candida tropicalis and the newly identified (1995) species of Candida dubliniensis (Dublin, Ireland)2 have also been associated with most forms of candidiasis. Fungal infections are frequently recognized, especially in patients with risk factors including cystic fibrosis, long term antibiotic therapy, prolonged critical care admission, and immunosuppression.3 Fungal involvement of the biliary tract seems to occur more often nowadays, probably due to the greater use of biliary interventions, both endoscopic and percutaneous.4 Data concerning the microbiological flora of the biliary tract are scarce, probably due to methodological limitations.4 Although bile analysis is useful to guide the therapeutic procedures in patients with biliary infections, few studies performed a microbiological analysis of bile in patients with different biliary diseases (Figure 1).Figure 1 Light microscopy for histopathology smears of infected bile (400×), (A) budding yeast (B) Candida albicans demonstrating chlamydospores (arrow 1), blastospores (arrow 2) and pseudohyphae (arrow 3).
Table 1 Clinical Course, Management and Outcome of Patients
Patient No.1 Patient No.2 Patient No.3 Patient No.4 Patient No.5
Fungus species Candida albicans Candida glabrata Candida albicans Candida albicans Candida albicans
Antifungal treatment Fluconazole “systemic” 200mg/day
Twice -daily drain flush with 100mg fluconazole Fluconazole,systemic 200mg/day
Twice -daily drain flush with 100mg fluconazole Fluconazole,systemic 200mg/day
Systemic Caspofungin
Twice -daily drain flush with 100mg fluconazole Systemic,Fluconazole Fluconazole “systemic” 200mg/day
Twice -daily drain flush with 100mg fluconazole
Fungal eradication Yes, after 10 days Yes, after 2 months No eradication after 6 months. Yes, after 2 weeks Yes after 5 weeks
Interventions - ERCP* attempted and failed.
-PTC**: internal external drainage
- PTC: metallic stent with external drainage.
-PTC: removal of drainage. - ERCP: failed and complicated by duodenal perforation.
- PTC: internal external drainage for persistent jaundice.
- PTC: metallic stent deployed, drainage kept in place.
- Whipple’s surgery
- PTC: stent with external drainage due to postoperative bile leak and anastomotic stricture.
- PTC: stent removed - ERCP: insertion of rubber stent at another hospital before presenting to us.
- PTC: internal external drainage.
- multiple PTC procedures for replacement and repositioning of drains. -ERCP attempted and failed.
-PTC: internal external drainage.
- PTC: metallic stent deployed, drain removed. -ERCP failed.
-PTC: internal external drainage.
- multiple PTC procedures for replacement and repositioning of drains.
- PTC: metallic stent deployed, drain removed.
Following interventions Chemotherapy Chemotherapy None Chemotherapy Chemotherapy
Survival after presentation Alive after 5 months Death after 15 months Death after 6 months Death after 6 months Death after 7 months
Abbreviations: *ERCP, endoscopic retrograde cholangiopancreatography; **PTC, percutaneous transhepatic cholangiogram.
Table 2 Clinical and Demographic Features of Patients
Patient No. Age Gender Clinical Presentation Primary Diagnosis Disease Stage (Radiologic) Comorbidities
1 71 Male Obstructive jaundice Gallbladder Cancer Extensive distant lymph node involvement and mesenteric deposits Previous History of urinary bladder Cancer
2 51 Male Obstructive jaundice Adenocarcinoma of the head of the pancreas No evidence of metastasis Stage 1b Smoker, FAP mutation with history of colectomy
3 54 Male Obstructive jaundice, abdominal pain Distal cholangiocarcinoma Pleural and lungs metastasis Diabetes Mellitus
4 40 Male Obstructive jaundice, epigastric pain Advanced gastric cancer Liver metastasis and extensive Lymph node involvement Smoker
5 63 Male Obstructive jaundice, epigastric pain Adenocarcinoma of the head of the pancreas Multiple liver metastatic lesions Hypertension
Abbreviation: FAP, familial adenomatous polyposis.
Despite the emerging awareness of biliary candidiasis, its clinical relevance and potential risk factors remain debatable The terms “Biliary candidiasis” or “Biliary mycosis” are alternatively used when candida species is detected in microbiological bile fluid analysis, with or without cholangitis. However, it is still controversial whether positive bile analysis represents fungal infection or colonization, and how the results should impact the therapeutic approach. In this study, we review cases of biliary candidiasis in the setting of biliary or regional malignancy, highlighting the potential correlation between biliary candidiasis and malignancy. Additionally, we describe the role of fungus balls in frequent biliary stent occlusion.
Patients and Methods
Study Design
This is a retrospective study in which we identified patients who underwent percutaneous trans-hepatic cholangiogram (PTC) for obstructive jaundice between January 2015 and January 2019. The results of bile cultures for all patients were examined.
Inclusion Criteria
Only patients with fungus growth in bile cultures were included. The medical records of these patients were reviewed, and definitive diagnosis, management protocols, and outcomes were described.
Ethics
The study protocol was reviewed and approved by the Institutional Review Board at King Abdullah University Hospital and by the Committee of Research on Human Subjects at the Jordan University of Science and Technology. (Non-funded research No: 20200438). We protected Patients’ confidentiality in accordance with declaration of Helsinki provisions. Written informed consent was obtained from the patients for the inclusion of their clinical data within this work.
Procedures
Endoscopic retrograde cholangiopancreatography (ERCP), as the intervention of choice, was attempted by an experienced gastroenterologist in those 5 patients. Inability to achieve biliary access in those patients through ERCP was attributed to the high-grade blockage of the distal portion of the common bile duct.5
Therefore, PTC was performed next, in which the level of obstruction was demonstrated, bypassed, and balloon-dilated. Bile samples for cultures for bacteria and fungi were obtained, and biopsies and/or brush cytology were taken. Occasionally, Candida pseudohyphae were directly observed on bile smears. We submitted samples for fungal culture in patients with a high-grade obstruction or prolonged jaundice. The specimens were cultivated both on Kimmig agar plates and in Sabouraud bouillons and additional delineation was performed by micromorphological and biochemical methods.
During initial PTC, internal plastic stents were placed without the routine use of external drainage, given that distal contrast runoff was smooth and free. After stent placement, an initial drop in cholestatic indices (direct bilirubin, alkaline phosphatase, gamma-GT) level was observed in nearly all patients, but then it spiked again in 48 to 72hrs. A repeat PTC confirmed partial or complete blockage of the stent with filling defects (fungus balls) in the common bile duct (Figure 2). Therefore, bile samples were resubmitted and an internal-external biliary drain was left in place. The daily drainage through the external catheter ranged from one to two liters, indicating persistent or recurrent occlusion. Multiple PTC stent revisions were necessary for several patients as shown in Table 1.Figure 2 Common bile duct stent partial occlusion with filling defects (fungus balls) at the tip of the black arrow.
Following the diagnosis of fungal cholangitis with direct visualization of pseudohyphae in smears or positive culture growth, we started systemic antifungals with fluconazole 200mg/day and twice-daily drain flush with 100mg of fluconazole until repeat culture showed no growth.
Results
A total of 71 patients (mean age: 55.8, M: F 5:0) with obstructive jaundice underwent PTC between January 2015 and January 2019. Only 5 patients (7%) had candida growth on PTC-obtained bile cultures (4 Candida albicans, 1 Candida glabrata). Two patients were diagnosed with cholangiocarcinoma, one with adenocarcinoma of the head of the pancreas, one with gallbladder cancer, and one with gastric adenocarcinoma. The patient with pancreatic adenocarcinoma experienced fungal cholangitis, which was successfully eradicated, and then he underwent a pancreaticoduodenectomy (Whipple’s procedure). The rest of the patients had metastatic disease at the time of diagnosis and were referred -after fungus eradication- for chemotherapy. Table 2 summarizes the clinical and demographic features of our cases. Patients’ comorbidities, disease staging, treatment options, and outcomes are illustrated in Table 1. Formation of fungal membranes predisposed to frequent drain clogging. Eradication was achieved in 4 patients after 10 days, 2 months, 2 weeks, and 3 weeks. One patient died after 6 months with persistent candida growth and frequent stent occlusion. Concerning the other 4 patients, chemotherapy delay intervals correlated with the aforementioned eradication periods.
Discussion
In this series, although we cultured candida species in 7% of patients undergoing PTC, we demonstrated that all patients with biliary candidiasis are found to have biliary or regional malignancy. In spite of the fact that other predisposing factors –including immunodeficiency, biliary instrumentation, and prolonged stagnation due to stricture- contribute to fungus overgrowth inside bile ducts, this rare infection was alarming for the presence of cancer.
Fungal cholangitis, as a form of Invasive candidiasis, is a leading cause of sepsis (candidemia) in this population, ie; patients with locoregional malignancies. Given the high cost of antifungal drugs, the potential for toxicity with prolonged use, and the poorer outcomes associated with delayed therapy; it is highly recommended that clinical microbiology as well as infectious diseases services are incorporated in the diagnosis and management of invasive candidiasis. The guidelines published by National Institute for Health and Care Excellence (NICE)6 along with 2019 updates on the core elements of hospital antibiotic Stewardship programs, both emphasized the importance of tracking, monitoring, and reporting of antimicrobial impact and outcomes.7
Welch has first described microbial presence in bile more than 130 years ago when Bacteria implication in gallstone pathogenesis was revealed.8,9 Pathogens may enter the biliary tree by a retrograde ascent from the duodenum -where 100–1000 bacteria live in each 1 milliliter of its’ lining mucosa- or from portal venous blood or during instrumentation of CBD.10
Because of the existence of biliary sphincter, bile flow, and some bile components that have antibacterial features, such as bile acids and immunoglobulin A (IgA), many authors suggest that bile in the biliary tract would be normally sterile unless the bile ducts are obstructed, or stones are present.11 On the contrary, multiple bacterial strains that can grow in bile (bile-tolerant) have been recently identified with the application of next-generation sequencing.12 These strains may induce chronic infection with possible malignant transformation (eg Helicobacter species, Hemophilus influenzae, E. coli).13
Moreover, in a study of 19 bile samples obtained during surgery from patients with a normal biliary tree (no stones or obstruction), there was positive growth in 16/19 samples for bacteria which led to a conclusion that human bile is not, as first thought, sterile.14
Most studies were conducted on abnormal biliary systems or unhealthy individuals. To make more reliable conclusions on the normal flora of the biliary system we believe that further studies of the normal biliary system of healthy individuals are warranted. However, this type of study may face technical challenges or ethical barriers. Therefore, we recommend obtaining bile cultures in all cases of biliary obstruction, and we believe that fungus growth in bile cultures obtained by PTC is of clinical significance.
In patients with obstructive jaundice, ERCP is usually attempted first. According to the American Society for Gastrointestinal Endoscopy (ASGE) guidelines,15 ERCP is the intervention of choice due to its advantage of drainage without the need for an external catheter. However, ERCP has a failure rate of 10–15%.16 Common reported causes of ERCP failure include duodenal diverticula, which increases with age, adhesions due to previous upper abdominal surgery or gastrointestinal diversions, or to a less extent obstruction due to tumors.17 The failure rate increases by 78-fold in patients with periampullary tumors that infiltrate the ampulla of Vater. Hence, PTC is a suitable alternative, especially in patients with a hilar obstruction or surgically-altered anatomy.18
Since bile samples from PTC are less prone to contamination by intestinal flora than ERCP samples, cultures from PTC samples are more reliable for an accurate diagnosis and antimicrobial selection.19
Several studies10,20,21 have investigated biliary candidiasis in terms of clinical presentation, diagnosis, and treatment modalities. However, only a few studies have analyzed its correlation with malignancy22 and the impact on patient outcomes, including survival rates. In a study by Kim and colleagues,18 Candida species were found in 23% of bile samples collected during PTC from patients with cholangiocarcinoma; Patients with biliary candidiasis had reduced survival compared to those without, the authors suggested that biliary candidiasis is a factor of poor prognosis. Reduced survival is probably attributed to factors such as sepsis, poor oral intake, complications of frequent invasive interventions, and delayed surgery or chemotherapy.
In another study by Lenz and colleagues,4 in which bile samples were collected during ERCP, Candida was isolated in 30% of patients. However, all patients suffered from severe chronic diseases and required frequent intervention; the authors found in a multivariate analysis that previous endoscopic sphincterotomy -which eliminates an important protective mechanism- was a significant risk factor for biliary candidiasis.
Other studies have demonstrated that fungus balls could be responsible for frequent CBD and stent occlusion. Story and Gluck23 described the soft filling defects within the bile duct. They also outlined the treatment approach, which consisted of daily oral antifungal and daily antifungal flushing through PTC external drain or cholecystostomy tube. In that study, the proposed treatment succeeded in the eradication of the infection in about 75% of cases.
In the present study, the diagnosis of fungal cholangitis preceded that of malignancy, suggesting that biliary candidiasis could be a warning sign of an underlying malignancy. We also highlight the role of fungus balls in frequent stent occlusion after PTC or ERCP, which is a rare but potentially treatable condition. Additionally, we emphasize the role of combined (systemic and intra-biliary) antifungal therapy in eradicating the pathogen. Our results suggest that biliary candidiasis could be associated with a worse prognosis.
This study has some limitations. Firstly, it is a retrospective study. Secondly, the sample size of patients with biliary candidiasis was too small to evaluate risk factors with statistical significance. Thirdly, many patients who did not have their bile cultures obtained may still have the infection, leading to some false-negative cases. Despite these limitations, the findings in this study contribute to the understanding of cancer association with biliary candidiasis and the importance of the implementation of an appropriate treatment approach.
In Conclusion, sampling bile for culture is recommended in patients with obstructive jaundice. Biliary candidiasis should raise concerns of underlying biliary or regional malignancy, in particular in the absence of other risk factors. Persistent cholestasis after biliary drainage may be attributed to fungus growth in the form of fungal balls, which may delay treatment by chemotherapy or surgery. Future prospective studies are warranted to investigate the putative association between biliary candidiasis and malignancy.
Disclosure
The authors report no conflicts of interest for this work. | Fatal | ReactionOutcome | CC BY-NC | 33707962 | 19,814,211 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastric polyps'. | Large Fundic Gland Polyp Associated with Long-Term Proton Pump Inhibitor Administration Mimicking Gastric-Type Neoplasm.
A 57-year-old man with a 10-year history of proton pump inhibitor (PPI) use presented with multiple fundic gland polyps (FGPs) including one >20 mm, whitish, semi-pedunculated polyp. Black spots and cobblestone-like mucosa were also observed in the stomach upon endoscopy; therefore, the lesion was considered to result from long-term PPI administration. Endoscopically, we diagnosed this polyp as a neoplastic lesion with gastric phenotype rather than a non-neoplastic lesion. Biopsy revealed an atypical glandular lesion that was indeterminate for neoplasia; therefore, we performed en bloc resection via endoscopic submucosal dissection (ESD) of the 22 × 22 × 10 mm-sized polyp. Histologically, the polyp was composed of hyperplastic foveolar epithelia in the upper half of the mucosa and hyperplastic fundic glands in the lower half of the mucosa, with luminal dilatation and parietal cell protrusion. The pathological diagnosis for this ESD specimen was FGP associated with PPI administration. We herein describe this rare case of a large FGP in Helicobacter pylori-uninfected gastric mucosa associated with long-term PPI administration, which was mimicking gastric-type neoplasm and resected by endoscopy.
Introduction
Proton pump inhibitors (PPIs) are considered relatively safe drugs and are widely used. However, after long-term PPI administration, the gastric mucosa may develop fundic gland polyps (FGPs), black spots, and cobblestone-like mucosa [1, 2]. Pathologically, hyperplasia of parietal cells and parietal cell protrusion into the lumen are typical findings [3]. Although hypoacidity and hypergastrinemia increase the risk of gastric cancer in the corpus and fundus [4, 5], the relationship between long-term PPI administration and tumor development remains unclear. Herein, we report the rare case of a 22 × 22 × 10 mm FGP in Helicobacter pylori (H. pylori)-uninfected gastric mucosa associated with long-term PPI administration that was mimicking gastric-type neoplasm and resected via endoscopy.
Case Report
A 57-year-old Japanese man had been taking lansoprazole for at least 10 years for gastroesophageal reflux. He had no new symptoms and no major medical history. Upper gastrointestinal endoscopy conducted for routine screening revealed multiple hydrops-like FGPs in the background mucosa without atrophy. A semi-pedunculated polyp >20 mm in size with black spots on the surface was found on the posterior wall of the greater curvature of the stomach (Fig. 1). In narrow-band imaging magnifying endoscopy (NBI-ME), the microsurface pattern showed circular gland duct openings in some areas, though the pattern was obscure in parts of the lesion. The microvascular pattern showed an enlarged blood vessel that ran laterally on the surface in most of the lesion. In addition, microvessels presenting tortuosity and slight dilatation were recognized in the parts where the microsurface pattern was obscure, although no caliber change or shape variations were noted (Fig. 2). Based on these endoscopic findings, we diagnosed this polyp as a neoplastic lesion with gastric phenotype rather than a non-neoplastic lesion. Biopsy results confirmed an atypical glandular lesion that was indeterminate for neoplasia. Therefore, we performed en bloc resection by endoscopic submucosal dissection (ESD) using a dual knife (Olympus Co., Ltd., Tokyo, Japan). Macroscopically, the lesion was a semi-pedunculated polyp that was 22 × 22 × 10 mm in size (Fig. 3). Histologically, the polyp was composed of hyperplastic foveolar epithelia in the upper half of the mucosa and hyperplastic fundic glands in the lower half of the mucosa, with luminal dilatation and parietal cell protrusion, which is typical of PPI-related FGPs (Fig. 4). No structural or cytological atypia was observed in the lesion and it was pathologically diagnosed as an FGP associated with PPI administration.
The patient had no history of H. pylori eradication, and H. pylori antibody and stool H. pylori antigen were both negative, which suggests no prior H. pylori infection of the gastric mucosa. As such, this large FGP associated with PPI administration was considered to have developed in H. pylori-uninfected gastric mucosa.
Discussion
In this case, the patient presented with a large FGP which was determined to result from extended PPI use. FGPs may occur sporadically or in association with syndromes such as familial adenomatous polyposis (FAP). Sporadic FGPs have been reported in 0.8–1.9% of patients undergoing esophagogastroduodenoscopy, and their occurrence has been associated with prolonged use of PPIs [6]. In our case, there was no clinical or colonoscopic evidence of FAP. Therefore, the lesion in our case was sporadic. In addition, the ESD specimen in this case demonstrated fundic gland hyperplasia and parietal cell protrusion, which have been widely observed in patients with long-term PPI administration. Therefore, our case was considered a PPI-related lesion. A report from Japan [7] indicated that 13.6% of patients developed new FGPs after rabeprazole administration for 104 weeks. These developed mainly in the corpus and were <5 mm. In this case, the 22 × 22 × 10 mm lesion was much larger than a common FGP. Although the mechanism of such large, sporadic FGP growth over long-term observation is unknown, our case suggests that FGPs could enlarge with long-term administration of PPI.
Endoscopic changes after long-term PPI administration include FGPs, black spots, and cobblestone-like mucosa; however, there are few detailed reports about PPI-related polyps, and characteristic findings in NBI-ME have not been well investigated. In our case, we found two patterns via NBI-ME: one pattern that was consistent with an FGP and one pattern that demonstrated microsurface and microvascular irregularities. We were unsure whether this lesion was neoplastic because the microsurface pattern did not present irregularities typical of neoplasia and the microvascular pattern did not meet all four signs of neoplasia (dilatation, tortuosity, caliber change, and various shapes). These findings might have been caused by inflammation due to polyp size or location in the stomach. As mentioned above, it is sometimes difficult to endoscopically determine whether a large lesion is neoplastic or non-neoplastic.
In the present case, we selected ESD as the treatment strategy because this large semi-pedunculated polyp was suspected to be neoplastic based on endoscopic findings and the preoperative biopsy could not rule out neoplasm either. There are few reports of treatment for PPI-related gastric polyps; however, we found one report of endoscopic mucosal resection for a 10-mm FGP with low-grade dysplasia [8].
It is also sometimes difficult to pathologically differentiate large FGPs from gastric-type neoplasia by biopsy specimen because FGPs associated with PPI use might show slight atypia or dysplastic changes. Previous literature reported that FGPs were detected in 88% of FAP patients and were dysplastic in 41% of patients [9]. In contrast, low-grade epithelial dysplasia has been reported in sporadic FGPs; however, its prevalence is said to be extremely low (approximately 1%) [10]. One paper reported that an FGP with dysplasia did not transform into invasive cancer although the patient underwent 14 years of PPI therapy [11]. Follow-up data from 26 cases of sporadic FGP with low-grade dysplasia also suggested that these lesions might be indolent in nature [10]. The malignant potential of PPI-related FGPs remains to be elucidated.
In conclusion, we herein report a rare case of a large FGP in H. pylori-uninfected gastric mucosa associated with long-term PPI administration, which was mimicking gastric-type neoplasm and resected by endoscopy.
Statements of Ethics
The patient provided written informed consent for publication of data and images.
Conflict of Interest Statement
The authors declare that they have no conflicts of interest to disclose.
Funding Sources
None declared.
Author Contributions
Y. Ochiai wrote the draft of the research study. Y. Ochiai, D. Kikuchi, and S. Hoteya conducted the data acquisition and revised the draft. S. Ito and Y. Takazawa analyzed the pathological findings. S. Hoteya supervised this case report.
Fig. 1 White-light images of the lesion and background of the stomach. a, b A whitish elevated polyp with black spots on the surface. Hydrops-like whitish polyps (c) and cobblestone-like mucosa (d) are seen in the background.
Fig. 2 Images of the lesion by NBI-ME. a The entire lesion by unmagnified NBI-ME. b The anal side of the lesion in retroflex observation by unmagnified NBI-ME. c Magnified NBI-ME view of the area framed by the white solid box in b. d Magnified NBI-ME view of the area framed by the white dashed box in b. NBI-ME, narrow-band imaging magnifying endoscopy.
Fig. 3 Specimen resected by endoscopic submucosal dissection. a The resected lesion. b Green lines show the area of the lesion. c Side view of the resected lesion.
Fig. 4 Histological images of the lesion (hematoxylin and eosin staining). a The section of the lesion showing polypoid proliferation with cystic glands and mild foveolar hyperplasia. b Higher magnification of the area framed by the black solid box in a showing hyperplastic changes and parietal cell protrusion. | LANSOPRAZOLE | DrugsGivenReaction | CC BY-NC | 33708059 | 19,644,728 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug hypersensitivity'. | Acute Generalized Exanthematous Pustulosis with Multiple Organ Failure.
Acute generalized exanthematous pustulosis (AGEP) is a rare, self-limiting condition. It presents with sterile skin pustules. We present a middle-aged lady with fluid nonresponsive circulatory shock and multiple organ dysfunction secondary to AGEP.
Introduction
Acute generalized exanthematous pustulosis (AGEP) is a rare condition presenting with numerous small, nonfollicular, sterile skin pustules on an erythematous base. It can be accompanied by fever and leukocytosis, but their presence is not mandatory [1, 2]. These are usually self-limited [3]. We present the rare situation of severe AGEP, initially diagnosed as septic shock, requiring vasopressor support.
Case Report
A 50-year-old, morbidly obese female with a past medical history of hypertension, hyperlipidemia, polycystic ovary syndrome, and obstructive sleep apnea on CPAP presented to the emergency department with high-grade fever (39.5°C), tachycardia (118 bpm), diarrhea, leukocytosis (11,000/mm3) with left shift, acute renal failure, and liver dysfunction (Table 1). She was prescribed amoxicillin at urgent care for suspicion of tick bite 8 days previously as she was allergic to doxycycline. Upon examination, she was found to have confluent erythema described as tiny pustules forming lakes of pus on her chin, cheeks, upper neck, and hairline and just below the ear, as well as diffuse hives on the back and face (Fig. 1, 2). There was no hemorrhagic crusting, and Nikolsky's sign was negative. The mucous membranes were spared. The genital region showed no visible ulcers. Over the next few hours, she experienced fluid-nonresponsive hypotension. She needed elective intubation due to increased work of breathing and respiratory fatigue. She also required blood pressure support with norepinephrine. With a working diagnosis of septic shock, she received intravenous fluids and antibiotics, including ceftriaxone, metronidazole, and levofloxacin. She also received intravenous bicarbonate followed by 2 sessions of hemodialysis for her acute renal failure causing severe metabolic acidosis.
As part of sepsis workup, multiple blood cultures turned out negative. Since the pustules were nonfollicular, bacterial folliculitis was less likely. A swab from the affected site showed normal skin commensals. The other principal noninfectious differential diagnoses included toxic epidermal necrosis/Steven-Johnson syndrome, pustular psoriasis, drug rash with eosinophilia and systemic symptoms, bullous impetigo, and other drug eruptions like the one associated with hydroxychloroquine [4]. The EuroSCAR study scoring system showed the diagnosis probably to be AGEP for our patient (Table 2).
Awaiting the results of the workup, the dermatologist indicated a clinical picture consistent with AGEP due to amoxicillin, and possibly potentiated by ceftriaxone. Though AGEP does not typically need systemic steroids, in this case, with liver and kidney dysfunction, the patient received intravenous methylprednisolone (100 mg once daily) for 3 days with discontinuation of antibiotics. Penicillin and cephalosporin were added to the patient's allergy list to prevent recurrence. Over the next 2 days, the patient's condition improved. Her vitals stabilized, she was extubated, and her rash began to clear with desquamation (Fig. 3). On day 9, she was discharged home. She received triamcinolone 0.1% cream for 2 weeks post-discharge and improved.
Discussion
AGEP is a rare cutaneous disorder [5]. It is mostly an adverse drug reaction, but other triggers are known. It has a female predominance [6]. AGEP is a type IV hypersensitivity reaction mediated by CD8+/CD4+ T cells. Histopathologically, we find spongiform subcorneal intraepidermal pustules. The clinical manifestation of AGEP consists of pin-sized sterile pustules on an erythematous base that start in the intertriginous areas and spread to the rest of the body [2]. There may be a sensation of itching or burning. AGEP is associated with fever and neutrophilic leukocytosis [3, 7]. After discontinuation of the causing drug, the skin lesions begin to resolve within 2 weeks with desquamation. Most of these cases are self-limiting with less than 5% mortality, but severe life-threatening cases needing ICU care and vasopressor support, as in our case, have been reported [2].
A diagnosis can be made by history-taking and examination in most cases. Usually, a patient presents with a history of taking an offending agent such as penicillin or cephalosporin. Pustules on an erythematous, edematous skin develop in about 5 days from initiation of the offending drug. The AGEP validation score generated by the EuroSCAR study group can be used to help in the diagnosis of AGEP [2]. The AGEP validation scoring system provides the probability of the diagnosis of AGEP. The categories include definite AGEP, probable AGEP, possible AGEP, and doubtful AGEP [8].
Based on this scoring system, the diagnosis in our patient was probable with a score of 6 (Table 2). The other differential diagnoses included septic shock, toxic epidermal necrolysis, Stevens-Johnson syndrome, and pustular psoriasis. Septic shock could be ruled out after a thorough infectious workup and inadequate response to antibiotics in this case. Toxic epidermal necrosis and Steven-Johnson syndrome were less probable as they involve the mucous membranes, unlike AGEP, which rarely involves the mucous membrane (Table 3) [1]. AGEP should also be differentiated from generalized pustular psoriasis. In pustular psoriasis, there is a past history of psoriasis; there might be other psoriatic skin lesions, the onset is slow, and the patient may get recurrent pustular eruptions. Also, beta-lactam antibiotics are a typical trigger of AGEP, in contrast to pustular psoriasis. AGEP is an acute, self-limiting disease. It is not associated with a history of psoriasis. Once the diagnosis of AGEP is established, a skin patch test may aid in determining the causative drug. It may be challenging to diagnose AGEP even with a skin patch test, since the sensitivity of the test is only 58% [2]. In such cases, a histopathological examination can be helpful.
Treatment is the immediate withdrawal of the offending medications such as beta-lactam antibiotics, macrolide, and cephalosporins [1]. Symptoms such as itching and fever can be controlled with topical steroids. Topical steroids decrease the duration of hospitalization [9]. Emollients may be used during the desquamation phase. If patients have extensive rashes, systemic steroids have been used [10]. Antibiotics are usually not required, but they may be needed in the event that the pustules get infected. This case is unique, as such a severe form of AGEP is extremely rarely encountered.
Conclusions
AGEP is a rare clinical condition that may be misdiagnosed. Usually, it is self-limiting, and withdrawal of the causative medication is the only treatment required in most of the cases. In severe cases, however, ICU admission, vasopressor support, and steroids may be needed.
Statement of Ethics
The patient has given written informed consent to publish this case, including the publication of images. The institute's committee on human research approved the manuscript. We avoided yielding information revealing the subject's identity. The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki (https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/).
Conflict of Interest Statement
The authors certify that they have no conflict of interest and no affiliations with or involvement in any organization or entity with any financial or nonfinancial interest in the subject matter or materials discussed in this manuscript.
Funding Sources
No funding was received.
Author Contributions
T.S.: case identification, manuscript writing, and informed consent. A.S.A., M.M., M.F.H.M., and R.A.: manuscript writing and literature review. Z.Y.: literature review, provided revisions to scientific content of the manuscript, and provided stylistic/grammatical revisions to the manuscript.
Fig. 1 Tiny pustules forming lakes of pus on the chin and cheeks.
Fig. 2 Tiny pustules forming lakes of pus around her hairline.
Fig. 3 Healing rash with desquamation.
Table 1 Investigations on admission and after recovery at discharge
Reference range Day 1 On the day of discharge (day 9)
Creatinine, mg/dL 0.50–1.10 4.18 (H) 0.69
Total bilirubin, mg/dL 0.3–1.2 0.9 0.6
AST, U/L 14–34 75 (H) 34
ALT, U/L 1–33 64 (H) 64 (H)
ALK PHOS, U/L 42–98 98 217 (H)
H, high.
Table 2 AGEP validation score by EuroSCAR study group − probable AGEP
Characteristic Our patient's lesions Score
Pustules Typical 2
Erythema Compatible 1
Distribution/pattern Typical 2
Postpustular desquamation Yes 1
Mucosal involvement No 0
Acute onset (≤10 days) Yes −2
Resolution ≤15 days Yes 0
Fever ≥38°C Yes 1
PMN ≥7,000/mm3 Yes 1
Histology No histology 0
Total score 6
Score ≥8: definite; score 5–7: probable; score 1–4: possible; score 0: doubtful. PMN, polymorphonuclear neutrophils.
Table 3 Acute generalized exanthematous pustulosis (AGEP) vs. toxic epidermal necrolysis (TEN)
AGEP TEN
Lesion Erythematous plaques, papules and pustules Dusky papules/plaque associate with sloughing
Mucosal involvement Rare Yes
Prognosis Good Poor
Histopathological examination Subcorneal neutrophilic pustules Full-thickness epidermal necrosis with bulla
Treatment Prompt withdrawal of offending drug Supportive care Topical steroids Prompt withdrawal of offending drug Supportive care Systemic steroids | DOXYCYCLINE | DrugsGivenReaction | CC BY-NC | 33708082 | 20,009,893 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhage intracranial'. | A 56-Year-Old Woman with Recurrent Strokes: A Clear Case with a Therapeutic Dilemma.
A 56-year-old woman with a history of cerebral amyloid angiopathy (CAA) complicated by prior intracranial hemorrhage (ICH) was evaluated for an asymptomatic ischemic stroke discovered on screening brain MRI. On echocardiogram, she was found to have a mass on her mitral valve and strongly positive antiphospholipid antibodies. She was diagnosed with nonbacterial thrombotic (Libman-Sacks) endocarditis associated with the primary antiphospholipid syndrome (APS). The treatment decision was complicated by the history of CAA with ICH within the last year with very high risk for bleeding complications if on anticoagulation. A multidisciplinary decision was made to initiate a trial of warfarin for 3 months. She fared well and warfarin was continued. She has not had any further bleeding or ischemic events over the subsequent 1.5 years and remains on warfarin for her APS.
Introduction
Patients with both cerebral amyloid angiopathy (CAA) and antiphospholipid antibody syndrome (APS) pose a therapeutic challenge for clinicians due to their inherent risks of hemorrhage and ischemic strokes, respectively. Decisions to start anticoagulation should be based on personalized risk and benefits of the conditions and treatment. Clinical and radiologic monitoring are important during treatment of concurrent CAA and APS. Further studies are needed to evaluate the safety of anticoagulation in patients with CAA.
Case Report
A 56-year-old Caucasian woman with a history of hypertension and migraine headaches was found by her husband walking in circles and acting strangely. She was last acting normally the night before and there were no signs of trauma. She was evaluated in an emergency department and found to have an intracerebral hemorrhage (ICH) in the left frontal cortex on head CT (Fig. 1). She had a history of mild hypertension but had not been on antihypertensive therapy.
She had not taken any anti-thrombotic medications prior to the ICH except for occasional aspirin-containing migraine therapy. Her coagulation profile was normal except for elevated activated partial thrombin time (aPTT). CT angiogram and MR angiogram did not detect any abnormal blood vessels. MRI of the brain did not show an underlying tumor or infarction. She was discharged on a low-dose antihypertensive agent. A repeat MRI of the brain was done a month later (Fig. 2) and showed 9 microhemorrhages and superficial siderosis meeting the Boston criteria for probable CAA [1]. Five months after the ICH, a repeat brain MRI showed a new area of encephalomalacia in the left occipital cortex that was not present on the prior MRI (Fig. 3). The radiological features indicated a chronic infarction [1]. The MRI also showed an area of encephalomalacia of the right frontal cortex/subcortex that had been seen on the initial CT and MRI but had unclear significance. With the development of the left occipital encephalomalacia, it became apparent that the right frontal lesion was also a chronic infarction. A transthoracic echocardiogram was done as part of the ischemic stroke investigations and showed an echogenic structure on the atrial aspect of the anterior mitral leaflet. Transesophageal echocardiogram was done on the same day and showed a 6-mm, sessile, thickened mass on the mitral valve (Fig. 4). She was admitted to the hospital for expedited workup. She was asymptomatic, did not show any systemic manifestations of infective endocarditis, and had normal vital signs. Her laboratory tests were significant for mild leukopenia, thrombocytopenia, and mild renal insufficiency. She also was noted to have aPTT of 54 s (normal: 22.5–36.5 s). Further hypercoagulable workup revealed positive lupus anticoagulant (LA), high-titer anticardiolipin (aCL) IgG antibody, and high-titer beta-2-glycoprotein 1 IgG antibody (aB2GP1) suggestive of APS. Additional autoimmune evaluation revealed low-titer ANA 1:40 and hypocomplementemia. The patient was diagnosed with nonbacterial thrombotic (Libman-Sacks) endocarditis due to primary APS. She did not meet criteria for another connective tissue disease. After multidisciplinary discussion regarding her underlying CAA and recent ICH, anticoagulation with warfarin was recommended for at least 3 months with INR goal of 2–3.
After 3 months on warfarin with INR documented between 1.6–2.6, a follow-up transthoracic echocardiogram showed a slightly smaller mass on the mitral valve. Anticoagulation was continued due to the persistent mass, as well as lack of adverse events. Repeat testing at that time for antiphospholipid antibodies (aPL) showed they were present in high titer confirming the diagnosis of APS. Indefinite anticoagulation was recommended.
In the one and half years since her initiation on warfarin, our patient has not had any major bleeding or thrombotic events, including intracranial bleeding. She has mild cognitive impairment without focal findings. Her most recent brain MRI, completed 18 months after the ICH, showed no new areas of ischemia or lobar hemorrhages, although there were 4 new microhemorrhages compared to the prior study (Fig. 5). No symptoms of another collagen vascular disease have developed.
Discussion
CAA is a condition characterized by amyloid deposition primarily in the walls of central nervous system arteries, which leads to fragile blood vessels that are prone to rupture. It is usually a sporadic condition that occurs in elderly individuals but a hereditary form can present earlier in life and cause more severe manifestations [2]. Distribution of CAA lesions are classically in the periphery of occipital, frontal, temporal, and parietal lobes. This is in contrast to those hemorrhagic lesions seen secondary to hypertension, which tend to be more central and involving the deep brain structures [3, 4]. Clinically, CAA can present as sporadic lobar hemorrhages causing altered mental status, focal neurologic deficits, coma, or death. However, they may also present with asymptomatic microbleeds leading to progressive cognitive decline and dementia [2]. Patients with CAA have an average ICH recurrence rate of approximately 9% per year, though the specific risk varies depending on their CAA biomarkers [5, 6]. Clinical diagnosis can be difficult and a definitive diagnosis is only made with tissue biopsy. The Boston criteria for CAA diagnosis allow clinicians to make a probable diagnosis based on clinical presentation, age, and exclusion of alternative etiologies for hemorrhage [2]. Unfortunately, there is no treatment of CAA and at the present time, the goal is to minimize the risk of recurrent intracranial bleeding. This includes ensuring adequate blood pressure control and avoiding anticoagulation. Our patient meets the Boston diagnostic criteria for probable CAA. Although she had been diagnosed with mild hypertension and had not been on an antihypertensive agent prior to her ICH, CAA is probably the underlying pathology given the cortical location of the left frontal hemorrhage, the microhemorrhages, and the sparing of the deep grey brain tissue such as basal ganglia, thalamus, and brainstem.
APS is an autoimmune disease characterized by thrombosis and obstetrical events in the presence of aPL. Diagnosis involves the occurrence of a thrombotic event and the laboratory presence of aPL. The three most commonly tested autoantibodies include LA, B2GP1 antibodies, and aCL antibodies [7]. The diagnosis of APS requires at least one aPL to be present in a moderate-to-high titer with a repeat test at least 12 weeks later to confirm. Patients that are positive for all three aPL are considered “triple positive” and thought to be at the highest risk of events [7, 8]. In a cohort of triple positive APS patients the thrombotic event rate after 10 years was 44.2%. Anticoagulation significantly decreased the rate of recurrent thrombosis in these patients [7]. The cornerstone of treatment for APS is anticoagulation with a vitamin K antagonist and those with high-risk profiles are recommended to remain on anticoagulation indefinitely. The need for anticoagulation is even greater when a patient, such as the one described, has Libman-Sacks endocarditis, which itself is an independent risk factor for embolic phenomena [9].
This patient represents a clinical challenge. There are no clinical trials regarding use of anticoagulation for APS in patients with CAA, especially those with history of ICH. Guidelines for management of non-valvular atrial fibrillation in patients with CAA suggests stratifying the ischemic risk against hemorrhagic risk. Generally, if a patient has CAA, anticoagulation is usually associated with higher risk of ICH. However, if the clinician feels that the risk of ischemic stroke outweighs the risk of hemorrhage, then oral anticoagulation is favored [6]. The radiological finding of superficial siderosis was associated with the highest risk of recurrent ICH [6]. A meta-analysis evaluating the use of oral anticoagulants in patients with ICH found that resuming oral anticoagulants led to favorable outcomes after 1 year, including those categorized as lobar ICH related to CAA [10]. In our case, the decision to anti-coagulate was made based on our assessment that the presence of the mitral valve vegetation along with MRI finding suggestive of an embolic stroke was the higher risk condition compared to CAA. We also envisioned that better control of hypertension would provide more protection from recurrent ICH. Our patient had only one symptomatic ICH 5 months earlier and only trace superficial siderosis. The detection of another MRI lesion consistent with a silent ischemic stroke that was older than the ICH was also interpreted as evidence of higher ischemic risk. As well, brain MRI before initiation of anticoagulation did not show progression of CAA compared to the one done at the time of ICH. Repeat MRI 1 year after anticoagulation only showed a few microhemorrhages that had not been seen before.
In a patient with the rare association of CAA and APS, without randomized controlled trials, clinicians must individualize treatment based on the patient's overall thrombotic and hemorrhagic risk. Fortunately, our patient has done well with anticoagulation and has remained free of ischemic hemorrhage or ICH. We plan on continuing anticoagulation and monitoring the patient clinically and radiologically with MRI. If there is evidence of significant progression of CAA, which is expected with age, or any recurrent ICH, the therapeutic plan may need to change.
Conclusion
In patients with symptomatic CAA and high-risk APS, the decision to start anticoagulation is challenging. In the absence of clinical guidelines, multidisciplinary decision-making and personalized management based upon the risks and benefits of the conditions and the treatment are necessary to make the safest therapeutic choice.
Statement of Ethics
Patient is not identified by name in this paper. She has reviewed the manuscript in entirety, including MRI/CT imaging, and has approved its contents for accuracy. She has provided written informed consent for publication of this case report and any accompanying images. This case report did not require IRB approval.
Conflict of Interest Statement
Authors have no conflicts of interest.
Funding Sources
None.
Author Contributions
All authors listed have contributed to drafting, writing, and editing of the manuscript. Eric S. Miller: draft, writing, editing, submission. Haitham M. Hussein: editing, writing, figures. Elie Gertner: editing, final review.
Fig. 1 Initial CT scan of the head showing left frontal cortical intracerebral hemorrhage measuring 5.7 mL with surrounding vasogenic edema.
Fig. 2 Susceptibility-weighted imaging sequence of a brain MRI done 1 month after intracerebral hemorrhage showing the left frontal lobar hemorrhage (b–d), multiple microhemorrhages (yellow arrowhead) in the cortical and subcortical areas but not the deep grey matter, and superficial siderosis (blue arrow).
Fig. 3 Diffusion-weighted imaging (a), apparent diffusion coefficient (b) map, and fluid attenuated inversion recovery (c) sequences of an MRI done 5 months after the intracerebral hemorrhage showing the development of a left occipital encephalomalacia (yellow arrow) that was new compared to the prior MRI done 3 months earlier representing a chronic infarction. The images also show a right frontal cortical encephalomalacia that had been seen from on initial imaging and was of unclear significance until the left occipital encephalomalacia developed. At that point, the impression was that the right frontal encephalomalacia was probably a chronic infarction too.
Fig. 4 Transesophageal echocardiogram image showing a 6-mm, sessile, thickened mass (red arrowhead) on mitral valve. Left atrium (LA) and left ventricle (LV) are labeled.
Fig. 5 Susceptibility-weighted imaging sequence of a brain MRI done 18 months after the left frontal intracerebral hemorrhage (ICH) showed no new lobar hemorrhages although a few new microhemorrhages (yellow arrowhead) could be detected compared to the MRI done 1 month after the ICH. | ASPIRIN | DrugsGivenReaction | CC BY-NC | 33708101 | 19,527,436 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Rare nocardiosis in danish patient with diabetes.
We herein report a rare case that describes and visualizes nocardiosis in a patient with diabetes. The patient presented with recurring fever, gout, leg pain, frailty and muscular pain through nine months, before a core needle biopsi, from an abscess in the abdominal musculature, revealed Nocardia Paucivorans. A PET-CT-scan showed multiple muscular FDG-positive sites. Furthermore, he experienced serious side effects to Sulfametoxazole and Trimethoprim, the antibiotic of choice for this type of infection. He was then switched to Moxifloxacin and Ampicillin. Nocardia often presents as opportunistic infections, typically in patients with severe immunodeficiencies, such as HIV, use of high-dose corticosteroids, hematologic malignancies or immunosuppression following organ transplantation. This case illustrates how a patient with only relative immunodeficiency gets rare nocardiosis. Our sparse knowledge on clinical presentation is based on case-reports and treatment is empirical. Hence, a better understanding of the clinical presentation and treatment is important. Especially given the prospect, that the health care system faces a greater load of patients with diabetes and other immunodeficiencies in the future.
pmcIntroduction
This case report describes and visualizes infection with Actinomyces Naeslundii (AN) and Nocardia Paucivorans (NP), causing lung infection and multiple muscular abscesses, respectively.
Case-report
A 78 year old male, with a medical history of hypertension, atrial fibrillation, arthritis urica, insulin-dependent type-2-diabetes complicated by diabetic nephropathy and former cancer prostate, for which he had undergone treatment, was initially admitted in September 2018. He presented a history, over the past six months, of recurring fever, gout, leg pain, frailty, alongside muscular pain from right humeral, and abdominal musculature.
The initial diagnostic CT-imaging showed a pulmonary infiltrate. The patient responded clinically and biochemically on antibiotic treatment, however, a 6 week control scan showed progression of the infiltrate. Hence, the patient underwent additional diagnosing with PET-CT, bronchoscopy, and core needle biopsy (CNB). PET-CT showed multiple muscular abscesses (Figure 1). AN was found in fluid from bronchoalveolar lavage and CNB from the lung did not confirm malignity. Only CNB from the abdominal musculature was positive for bacterial growth, namely NP. The patient was HIV negative and had normal levels of immunoglobulins.Figure 1. First PET-CT scan, November 2018
During medical examinations, the patient was treated with Piperacillin/Tazobactam and Metronidazole. After discovering NP, antibiotic treatment was adjusted to Sulfametoxazole and Trimethoprim (STM). However, three weeks later, the patient was submitted with bradycardia, acute kidney failure and myelosuppression, most likely side effects to STM. After normalization of bone marrow function, the antibiotic strategy was changed to Amoxicillin and Moxifloxacin. Regular PET-CT and blood sampling over additionally nine months showed sporadic and slowly regression of the abscesses. A year after first submitted the patient was without any muscular complaints. This lead to pause of antibiotics, which two months later, resulted in progression of the original lung foci. BAL was now positive for Actinomycis Odontolyticus (AO), which in writing, is treated with high doses of penicillin.
Discussion
This patient was infected with both AN and NP. Pulmonary infection with AN is likely due to aspiration of infected oral material, given this agent’s natural presence in the mucosal barrier of the oral cavity. It is likely that the AO infection of the lung was acquired through the first bronchoscopy. Conversely, Nocardia normally thrives in organic matter, and human infections are acquired by either inhalation or skin laceration [1]. We suspect the latter to have been the way of contamination, since Nocardia was found in the abdominal rectus musculature, suggesting, that the patient has used a contaminated needle during insulin administration.
Both AN and NP are capable of hematogen spread and can present with abscesses and fever. The presence of NP could only be identified in the abdominal abscess, so whether we have to do with disseminated NP or AN infection in this case, is difficult to say. PET-CT scans show a relatively quick pulmonary response to antibiotic treatment, compared to a generally more vague response in the muscular foci (Figures 1–3). These circumstances lead us to suspect disseminated NP infection. However, we cannot exclude that AN has been the cause of fever for this patient in some cases.Figure 2. PET-CT, March 2019. Note the quick pulmonary response, against the more vague muscular response
Figure 3. PET-CT, Juni 2019. Muscular foci are clearly in regression
Malignancy is a relevant differential diagnosis to infections with low pathogenic microorganism such as fungi, mycobacteria or, as in this case, actinomycetales. Clinically it can be hard to distinguish between them. The brief clinically and biochemically response to antibiotics in this case, together with PET-CT scans, supports the infection suspicion. If the physician suspects infection with the above-mentioned pathogens, the microbiological department must be notified, since these pathogens need either special media, circumstances (temperature, pH etc.) or longer time for growth.
Nocardia often presents as opportunistic infections, typically in patients with severe immunodeficiencies, such as HIV, use of high-dose corticosteroids, hematologic malignancies or immunosuppression following organ transplantation. But infections in immunocompetent patients and lung colonization in patients with COPD have been described [2,3]. The comorbidities of this patient are causing a relative immunodeficiency making him vulnerable to be infected with both AN and NP. Especially his diabetes must be considered a lead actor in this vulnerability, given that diabetes impairs the cellular immune system, which is vital for successful clearance of Nocardia infections [4].
Regarding prognosis, a review from 2020 presents, that for pleuropulmonary Nocardia infection approximately 80% are cured and only 3% with disseminated nocardiosis are cured [5].
This case illustrates how a patient with a common diagnosis such as diabetes gets infected with two opportunistic bacteria. Especially NP is rare. In addition, he did not tolerate first-line antibiotics for this type of infection. Our sparse knowledge on clinical presentation is based on case-reports and treatment is empirical. Hence, a better understanding of the clinical presentation is important, especially given the prospect, that the health care system faces a greater load of patients with diabetes and other immunodeficiencies in the future.
Cecilie Norup Thomsen, MD. Is a physician at the Department of Internal Medicine and Respiratory Diseases, at Holstebro Hospital, Hospital Unit West, Denmark.
Søren Sperling, MD. Is a physician, taking his rehsidency in Internal Medicine and Respiratory Diseases at Department of Internal Medicine, Holstebro Hospital, Hospital Unit West, Denmark and Department of Respiratory Diseases Aarhus University Hospital, Denmark.
Joan Fedelius, MD, PhD. Is a senior doctor with specialty in Radiology, working at the Department of Nuclearmedicine, Herning, Hospital Unit West.
Pia Holland Gjørup, MD, PhD. Is a senior doctor with specialty in Internal Medicine and Respiratory Diseases, working at the Department of Internal Medicine, Holstebro, Hospital Unit West, Denmark
Disclosure statement
The authors report no conflict of interest. | SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC | 33708362 | 19,084,690 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bradycardia'. | Rare nocardiosis in danish patient with diabetes.
We herein report a rare case that describes and visualizes nocardiosis in a patient with diabetes. The patient presented with recurring fever, gout, leg pain, frailty and muscular pain through nine months, before a core needle biopsi, from an abscess in the abdominal musculature, revealed Nocardia Paucivorans. A PET-CT-scan showed multiple muscular FDG-positive sites. Furthermore, he experienced serious side effects to Sulfametoxazole and Trimethoprim, the antibiotic of choice for this type of infection. He was then switched to Moxifloxacin and Ampicillin. Nocardia often presents as opportunistic infections, typically in patients with severe immunodeficiencies, such as HIV, use of high-dose corticosteroids, hematologic malignancies or immunosuppression following organ transplantation. This case illustrates how a patient with only relative immunodeficiency gets rare nocardiosis. Our sparse knowledge on clinical presentation is based on case-reports and treatment is empirical. Hence, a better understanding of the clinical presentation and treatment is important. Especially given the prospect, that the health care system faces a greater load of patients with diabetes and other immunodeficiencies in the future.
pmcIntroduction
This case report describes and visualizes infection with Actinomyces Naeslundii (AN) and Nocardia Paucivorans (NP), causing lung infection and multiple muscular abscesses, respectively.
Case-report
A 78 year old male, with a medical history of hypertension, atrial fibrillation, arthritis urica, insulin-dependent type-2-diabetes complicated by diabetic nephropathy and former cancer prostate, for which he had undergone treatment, was initially admitted in September 2018. He presented a history, over the past six months, of recurring fever, gout, leg pain, frailty, alongside muscular pain from right humeral, and abdominal musculature.
The initial diagnostic CT-imaging showed a pulmonary infiltrate. The patient responded clinically and biochemically on antibiotic treatment, however, a 6 week control scan showed progression of the infiltrate. Hence, the patient underwent additional diagnosing with PET-CT, bronchoscopy, and core needle biopsy (CNB). PET-CT showed multiple muscular abscesses (Figure 1). AN was found in fluid from bronchoalveolar lavage and CNB from the lung did not confirm malignity. Only CNB from the abdominal musculature was positive for bacterial growth, namely NP. The patient was HIV negative and had normal levels of immunoglobulins.Figure 1. First PET-CT scan, November 2018
During medical examinations, the patient was treated with Piperacillin/Tazobactam and Metronidazole. After discovering NP, antibiotic treatment was adjusted to Sulfametoxazole and Trimethoprim (STM). However, three weeks later, the patient was submitted with bradycardia, acute kidney failure and myelosuppression, most likely side effects to STM. After normalization of bone marrow function, the antibiotic strategy was changed to Amoxicillin and Moxifloxacin. Regular PET-CT and blood sampling over additionally nine months showed sporadic and slowly regression of the abscesses. A year after first submitted the patient was without any muscular complaints. This lead to pause of antibiotics, which two months later, resulted in progression of the original lung foci. BAL was now positive for Actinomycis Odontolyticus (AO), which in writing, is treated with high doses of penicillin.
Discussion
This patient was infected with both AN and NP. Pulmonary infection with AN is likely due to aspiration of infected oral material, given this agent’s natural presence in the mucosal barrier of the oral cavity. It is likely that the AO infection of the lung was acquired through the first bronchoscopy. Conversely, Nocardia normally thrives in organic matter, and human infections are acquired by either inhalation or skin laceration [1]. We suspect the latter to have been the way of contamination, since Nocardia was found in the abdominal rectus musculature, suggesting, that the patient has used a contaminated needle during insulin administration.
Both AN and NP are capable of hematogen spread and can present with abscesses and fever. The presence of NP could only be identified in the abdominal abscess, so whether we have to do with disseminated NP or AN infection in this case, is difficult to say. PET-CT scans show a relatively quick pulmonary response to antibiotic treatment, compared to a generally more vague response in the muscular foci (Figures 1–3). These circumstances lead us to suspect disseminated NP infection. However, we cannot exclude that AN has been the cause of fever for this patient in some cases.Figure 2. PET-CT, March 2019. Note the quick pulmonary response, against the more vague muscular response
Figure 3. PET-CT, Juni 2019. Muscular foci are clearly in regression
Malignancy is a relevant differential diagnosis to infections with low pathogenic microorganism such as fungi, mycobacteria or, as in this case, actinomycetales. Clinically it can be hard to distinguish between them. The brief clinically and biochemically response to antibiotics in this case, together with PET-CT scans, supports the infection suspicion. If the physician suspects infection with the above-mentioned pathogens, the microbiological department must be notified, since these pathogens need either special media, circumstances (temperature, pH etc.) or longer time for growth.
Nocardia often presents as opportunistic infections, typically in patients with severe immunodeficiencies, such as HIV, use of high-dose corticosteroids, hematologic malignancies or immunosuppression following organ transplantation. But infections in immunocompetent patients and lung colonization in patients with COPD have been described [2,3]. The comorbidities of this patient are causing a relative immunodeficiency making him vulnerable to be infected with both AN and NP. Especially his diabetes must be considered a lead actor in this vulnerability, given that diabetes impairs the cellular immune system, which is vital for successful clearance of Nocardia infections [4].
Regarding prognosis, a review from 2020 presents, that for pleuropulmonary Nocardia infection approximately 80% are cured and only 3% with disseminated nocardiosis are cured [5].
This case illustrates how a patient with a common diagnosis such as diabetes gets infected with two opportunistic bacteria. Especially NP is rare. In addition, he did not tolerate first-line antibiotics for this type of infection. Our sparse knowledge on clinical presentation is based on case-reports and treatment is empirical. Hence, a better understanding of the clinical presentation is important, especially given the prospect, that the health care system faces a greater load of patients with diabetes and other immunodeficiencies in the future.
Cecilie Norup Thomsen, MD. Is a physician at the Department of Internal Medicine and Respiratory Diseases, at Holstebro Hospital, Hospital Unit West, Denmark.
Søren Sperling, MD. Is a physician, taking his rehsidency in Internal Medicine and Respiratory Diseases at Department of Internal Medicine, Holstebro Hospital, Hospital Unit West, Denmark and Department of Respiratory Diseases Aarhus University Hospital, Denmark.
Joan Fedelius, MD, PhD. Is a senior doctor with specialty in Radiology, working at the Department of Nuclearmedicine, Herning, Hospital Unit West.
Pia Holland Gjørup, MD, PhD. Is a senior doctor with specialty in Internal Medicine and Respiratory Diseases, working at the Department of Internal Medicine, Holstebro, Hospital Unit West, Denmark
Disclosure statement
The authors report no conflict of interest. | SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC | 33708362 | 19,084,690 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myelosuppression'. | Rare nocardiosis in danish patient with diabetes.
We herein report a rare case that describes and visualizes nocardiosis in a patient with diabetes. The patient presented with recurring fever, gout, leg pain, frailty and muscular pain through nine months, before a core needle biopsi, from an abscess in the abdominal musculature, revealed Nocardia Paucivorans. A PET-CT-scan showed multiple muscular FDG-positive sites. Furthermore, he experienced serious side effects to Sulfametoxazole and Trimethoprim, the antibiotic of choice for this type of infection. He was then switched to Moxifloxacin and Ampicillin. Nocardia often presents as opportunistic infections, typically in patients with severe immunodeficiencies, such as HIV, use of high-dose corticosteroids, hematologic malignancies or immunosuppression following organ transplantation. This case illustrates how a patient with only relative immunodeficiency gets rare nocardiosis. Our sparse knowledge on clinical presentation is based on case-reports and treatment is empirical. Hence, a better understanding of the clinical presentation and treatment is important. Especially given the prospect, that the health care system faces a greater load of patients with diabetes and other immunodeficiencies in the future.
pmcIntroduction
This case report describes and visualizes infection with Actinomyces Naeslundii (AN) and Nocardia Paucivorans (NP), causing lung infection and multiple muscular abscesses, respectively.
Case-report
A 78 year old male, with a medical history of hypertension, atrial fibrillation, arthritis urica, insulin-dependent type-2-diabetes complicated by diabetic nephropathy and former cancer prostate, for which he had undergone treatment, was initially admitted in September 2018. He presented a history, over the past six months, of recurring fever, gout, leg pain, frailty, alongside muscular pain from right humeral, and abdominal musculature.
The initial diagnostic CT-imaging showed a pulmonary infiltrate. The patient responded clinically and biochemically on antibiotic treatment, however, a 6 week control scan showed progression of the infiltrate. Hence, the patient underwent additional diagnosing with PET-CT, bronchoscopy, and core needle biopsy (CNB). PET-CT showed multiple muscular abscesses (Figure 1). AN was found in fluid from bronchoalveolar lavage and CNB from the lung did not confirm malignity. Only CNB from the abdominal musculature was positive for bacterial growth, namely NP. The patient was HIV negative and had normal levels of immunoglobulins.Figure 1. First PET-CT scan, November 2018
During medical examinations, the patient was treated with Piperacillin/Tazobactam and Metronidazole. After discovering NP, antibiotic treatment was adjusted to Sulfametoxazole and Trimethoprim (STM). However, three weeks later, the patient was submitted with bradycardia, acute kidney failure and myelosuppression, most likely side effects to STM. After normalization of bone marrow function, the antibiotic strategy was changed to Amoxicillin and Moxifloxacin. Regular PET-CT and blood sampling over additionally nine months showed sporadic and slowly regression of the abscesses. A year after first submitted the patient was without any muscular complaints. This lead to pause of antibiotics, which two months later, resulted in progression of the original lung foci. BAL was now positive for Actinomycis Odontolyticus (AO), which in writing, is treated with high doses of penicillin.
Discussion
This patient was infected with both AN and NP. Pulmonary infection with AN is likely due to aspiration of infected oral material, given this agent’s natural presence in the mucosal barrier of the oral cavity. It is likely that the AO infection of the lung was acquired through the first bronchoscopy. Conversely, Nocardia normally thrives in organic matter, and human infections are acquired by either inhalation or skin laceration [1]. We suspect the latter to have been the way of contamination, since Nocardia was found in the abdominal rectus musculature, suggesting, that the patient has used a contaminated needle during insulin administration.
Both AN and NP are capable of hematogen spread and can present with abscesses and fever. The presence of NP could only be identified in the abdominal abscess, so whether we have to do with disseminated NP or AN infection in this case, is difficult to say. PET-CT scans show a relatively quick pulmonary response to antibiotic treatment, compared to a generally more vague response in the muscular foci (Figures 1–3). These circumstances lead us to suspect disseminated NP infection. However, we cannot exclude that AN has been the cause of fever for this patient in some cases.Figure 2. PET-CT, March 2019. Note the quick pulmonary response, against the more vague muscular response
Figure 3. PET-CT, Juni 2019. Muscular foci are clearly in regression
Malignancy is a relevant differential diagnosis to infections with low pathogenic microorganism such as fungi, mycobacteria or, as in this case, actinomycetales. Clinically it can be hard to distinguish between them. The brief clinically and biochemically response to antibiotics in this case, together with PET-CT scans, supports the infection suspicion. If the physician suspects infection with the above-mentioned pathogens, the microbiological department must be notified, since these pathogens need either special media, circumstances (temperature, pH etc.) or longer time for growth.
Nocardia often presents as opportunistic infections, typically in patients with severe immunodeficiencies, such as HIV, use of high-dose corticosteroids, hematologic malignancies or immunosuppression following organ transplantation. But infections in immunocompetent patients and lung colonization in patients with COPD have been described [2,3]. The comorbidities of this patient are causing a relative immunodeficiency making him vulnerable to be infected with both AN and NP. Especially his diabetes must be considered a lead actor in this vulnerability, given that diabetes impairs the cellular immune system, which is vital for successful clearance of Nocardia infections [4].
Regarding prognosis, a review from 2020 presents, that for pleuropulmonary Nocardia infection approximately 80% are cured and only 3% with disseminated nocardiosis are cured [5].
This case illustrates how a patient with a common diagnosis such as diabetes gets infected with two opportunistic bacteria. Especially NP is rare. In addition, he did not tolerate first-line antibiotics for this type of infection. Our sparse knowledge on clinical presentation is based on case-reports and treatment is empirical. Hence, a better understanding of the clinical presentation is important, especially given the prospect, that the health care system faces a greater load of patients with diabetes and other immunodeficiencies in the future.
Cecilie Norup Thomsen, MD. Is a physician at the Department of Internal Medicine and Respiratory Diseases, at Holstebro Hospital, Hospital Unit West, Denmark.
Søren Sperling, MD. Is a physician, taking his rehsidency in Internal Medicine and Respiratory Diseases at Department of Internal Medicine, Holstebro Hospital, Hospital Unit West, Denmark and Department of Respiratory Diseases Aarhus University Hospital, Denmark.
Joan Fedelius, MD, PhD. Is a senior doctor with specialty in Radiology, working at the Department of Nuclearmedicine, Herning, Hospital Unit West.
Pia Holland Gjørup, MD, PhD. Is a senior doctor with specialty in Internal Medicine and Respiratory Diseases, working at the Department of Internal Medicine, Holstebro, Hospital Unit West, Denmark
Disclosure statement
The authors report no conflict of interest. | SULFAMETHOXAZOLE\TRIMETHOPRIM | DrugsGivenReaction | CC BY-NC | 33708362 | 19,084,690 | 2021-02-24 |
What was the outcome of reaction 'Myelosuppression'? | Rare nocardiosis in danish patient with diabetes.
We herein report a rare case that describes and visualizes nocardiosis in a patient with diabetes. The patient presented with recurring fever, gout, leg pain, frailty and muscular pain through nine months, before a core needle biopsi, from an abscess in the abdominal musculature, revealed Nocardia Paucivorans. A PET-CT-scan showed multiple muscular FDG-positive sites. Furthermore, he experienced serious side effects to Sulfametoxazole and Trimethoprim, the antibiotic of choice for this type of infection. He was then switched to Moxifloxacin and Ampicillin. Nocardia often presents as opportunistic infections, typically in patients with severe immunodeficiencies, such as HIV, use of high-dose corticosteroids, hematologic malignancies or immunosuppression following organ transplantation. This case illustrates how a patient with only relative immunodeficiency gets rare nocardiosis. Our sparse knowledge on clinical presentation is based on case-reports and treatment is empirical. Hence, a better understanding of the clinical presentation and treatment is important. Especially given the prospect, that the health care system faces a greater load of patients with diabetes and other immunodeficiencies in the future.
pmcIntroduction
This case report describes and visualizes infection with Actinomyces Naeslundii (AN) and Nocardia Paucivorans (NP), causing lung infection and multiple muscular abscesses, respectively.
Case-report
A 78 year old male, with a medical history of hypertension, atrial fibrillation, arthritis urica, insulin-dependent type-2-diabetes complicated by diabetic nephropathy and former cancer prostate, for which he had undergone treatment, was initially admitted in September 2018. He presented a history, over the past six months, of recurring fever, gout, leg pain, frailty, alongside muscular pain from right humeral, and abdominal musculature.
The initial diagnostic CT-imaging showed a pulmonary infiltrate. The patient responded clinically and biochemically on antibiotic treatment, however, a 6 week control scan showed progression of the infiltrate. Hence, the patient underwent additional diagnosing with PET-CT, bronchoscopy, and core needle biopsy (CNB). PET-CT showed multiple muscular abscesses (Figure 1). AN was found in fluid from bronchoalveolar lavage and CNB from the lung did not confirm malignity. Only CNB from the abdominal musculature was positive for bacterial growth, namely NP. The patient was HIV negative and had normal levels of immunoglobulins.Figure 1. First PET-CT scan, November 2018
During medical examinations, the patient was treated with Piperacillin/Tazobactam and Metronidazole. After discovering NP, antibiotic treatment was adjusted to Sulfametoxazole and Trimethoprim (STM). However, three weeks later, the patient was submitted with bradycardia, acute kidney failure and myelosuppression, most likely side effects to STM. After normalization of bone marrow function, the antibiotic strategy was changed to Amoxicillin and Moxifloxacin. Regular PET-CT and blood sampling over additionally nine months showed sporadic and slowly regression of the abscesses. A year after first submitted the patient was without any muscular complaints. This lead to pause of antibiotics, which two months later, resulted in progression of the original lung foci. BAL was now positive for Actinomycis Odontolyticus (AO), which in writing, is treated with high doses of penicillin.
Discussion
This patient was infected with both AN and NP. Pulmonary infection with AN is likely due to aspiration of infected oral material, given this agent’s natural presence in the mucosal barrier of the oral cavity. It is likely that the AO infection of the lung was acquired through the first bronchoscopy. Conversely, Nocardia normally thrives in organic matter, and human infections are acquired by either inhalation or skin laceration [1]. We suspect the latter to have been the way of contamination, since Nocardia was found in the abdominal rectus musculature, suggesting, that the patient has used a contaminated needle during insulin administration.
Both AN and NP are capable of hematogen spread and can present with abscesses and fever. The presence of NP could only be identified in the abdominal abscess, so whether we have to do with disseminated NP or AN infection in this case, is difficult to say. PET-CT scans show a relatively quick pulmonary response to antibiotic treatment, compared to a generally more vague response in the muscular foci (Figures 1–3). These circumstances lead us to suspect disseminated NP infection. However, we cannot exclude that AN has been the cause of fever for this patient in some cases.Figure 2. PET-CT, March 2019. Note the quick pulmonary response, against the more vague muscular response
Figure 3. PET-CT, Juni 2019. Muscular foci are clearly in regression
Malignancy is a relevant differential diagnosis to infections with low pathogenic microorganism such as fungi, mycobacteria or, as in this case, actinomycetales. Clinically it can be hard to distinguish between them. The brief clinically and biochemically response to antibiotics in this case, together with PET-CT scans, supports the infection suspicion. If the physician suspects infection with the above-mentioned pathogens, the microbiological department must be notified, since these pathogens need either special media, circumstances (temperature, pH etc.) or longer time for growth.
Nocardia often presents as opportunistic infections, typically in patients with severe immunodeficiencies, such as HIV, use of high-dose corticosteroids, hematologic malignancies or immunosuppression following organ transplantation. But infections in immunocompetent patients and lung colonization in patients with COPD have been described [2,3]. The comorbidities of this patient are causing a relative immunodeficiency making him vulnerable to be infected with both AN and NP. Especially his diabetes must be considered a lead actor in this vulnerability, given that diabetes impairs the cellular immune system, which is vital for successful clearance of Nocardia infections [4].
Regarding prognosis, a review from 2020 presents, that for pleuropulmonary Nocardia infection approximately 80% are cured and only 3% with disseminated nocardiosis are cured [5].
This case illustrates how a patient with a common diagnosis such as diabetes gets infected with two opportunistic bacteria. Especially NP is rare. In addition, he did not tolerate first-line antibiotics for this type of infection. Our sparse knowledge on clinical presentation is based on case-reports and treatment is empirical. Hence, a better understanding of the clinical presentation is important, especially given the prospect, that the health care system faces a greater load of patients with diabetes and other immunodeficiencies in the future.
Cecilie Norup Thomsen, MD. Is a physician at the Department of Internal Medicine and Respiratory Diseases, at Holstebro Hospital, Hospital Unit West, Denmark.
Søren Sperling, MD. Is a physician, taking his rehsidency in Internal Medicine and Respiratory Diseases at Department of Internal Medicine, Holstebro Hospital, Hospital Unit West, Denmark and Department of Respiratory Diseases Aarhus University Hospital, Denmark.
Joan Fedelius, MD, PhD. Is a senior doctor with specialty in Radiology, working at the Department of Nuclearmedicine, Herning, Hospital Unit West.
Pia Holland Gjørup, MD, PhD. Is a senior doctor with specialty in Internal Medicine and Respiratory Diseases, working at the Department of Internal Medicine, Holstebro, Hospital Unit West, Denmark
Disclosure statement
The authors report no conflict of interest. | Recovered | ReactionOutcome | CC BY-NC | 33708362 | 19,052,115 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Obliterative bronchiolitis'. | Low-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study.
T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m2 daily for 5 days and repeated every 6-8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3-22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.
Introduction
Allogeneic stem cell transplantation (allo-HSCT) is a potentially curative therapy for malignant hematological diseases. Disease relapse remains a major cause of treatment failure (1, 2). The monitoring of disease-related parameters, such as measurable residual disease (MRD), can detect evidence of low-volume disease, which can serve as an indicator for emerging relapse (3). Hematopoietic chimerism analysis, which can distinguish residual recipient hematopoiesis from donor cells, is useful for the monitoring of allograft health and predicting imminent graft rejection, and can also be an indicator of potential relapse (2). The gold standard for quantitative chimerism analysis relies on the polymerase chain reaction (PCR)-based detection of variable number tandem repeats (VNTRs) or short tandem repeat (STR) polymorphisms in DNA from bone marrow or peripheral blood mononucleated cells or T cells, as recommended by the EuroChimerism Consortium (4–7).
Several studies have demonstrated that patients with mixed chimerism (MC) in either mononucleated cells or CD3+ T cells display a significantly higher incidence of relapse (40–90%) than those with complete donor chimerism (10–20%). The time between the detection of MC and relapse (median ~70 days) may permit timely therapeutic intervention (8–10). The rapid withdrawal of immunosuppression (RWIS) and preemptive donor lymphocyte infusion (DLI) may result in full donor chimerism (FDC) and are effective in reducing the relapse rate (RR) (11–14). However, RWIS and DLI have also been associated with complications, such as the development or aggravation of graft-versus-host disease (GvHD). Notably, MC without MRD does not necessarily equate to disease recurrence because the recrudescence of host hematopoiesis may represent normal hematopoiesis. In such a scenario, clinical decisions of immune modulation are complicated owing to the unnecessary risk of aggravation of GvHD (1, 2).
Epigenetic modulation of histone deacetylases (HDCs) such as sirturin-1 or methylation is important in maintaining normal function of hematopoietic stem cells and potentially regulating GvHD or graft versus leukemia effect (GvL) in the allo-HSCT settings (15–17). Hypomethylating agents (HMAs), administered either prophylactically or preemptively, are important treatment options after allo-HSCT for patients with acute myeloid leukemia (AML) or myelodysplasia (MDS) (18, 19). Multiple studies have demonstrated that HMAs exert significant immunomodulatory effects and are important for reducing post-transplantation relapse, and do so without inducing GvHD (20). In our previous study, we observed that low-dose decitabine (LD-DAC) converted MC into FDC in patients during maintenance therapy (21). In this pilot prospective study, we assessed the efficacy and safety of LD-DAC in the treatment of patients with MC in CD3+ T cells after allo-HSCT with myeloablative conditioning (MAC).
Methods
Study Design
This was an investigator-initiated, prospective, nonrandomized, single-arm, phase II clinical trial (NCT 03663751) to evaluate the efficacy and safety of LD-DAC as a monotherapy for patients with MC and who were also MRD-negative after allo-HSCT. The study was approved by the Human Ethics Committee of the Rui Jin Hospital and was conducted in accordance with the Declaration of Helsinki. The study was conducted in the Blood and Marrow Transplantation Center, Department of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. All enrolled patients provided written informed consent.
Study Protocol
The inclusion criteria were as follows: (1) adult patients (16–60) undergoing allo-HSCT with myeloablative conditioning from human leukocyte antigen (HLA)-matched sibling donors (MSDs), matched unrelated donors (MUDs), or haploidentical (Haplo) donors; (2) patients who achieved hematological engraftment and presented with a sustainable absolute neutrophil count (ANC) of >0.5 × 109/L not dependent on granulocyte colony-stimulating factor; (3) patients with hematological malignancies and presenting with measurable disease as indicated by immunophenotyping and/or molecular analysis; and (4) patients presented with MC (<99%) among T cells from either bone marrow or peripheral blood and who were MRD-negative in the bone marrow (<0.01%) after transplantation. The exclusion criteria were (1) patients with grade II-IV acute GvHD (aGvHD) or moderate to severe chronic GVHD (cGvHD) not responding to the treatment and (2) patients with severe complications such as life-threatening infections (bacterial, viral, or fungal), sinusoid obstructive syndrome (SOS), HSCT-associated thrombotic microangiopathy (TA-TMA), or posterior reversible encephalopathy syndrome (PRES) not responding to treatment.
All the enrolled patients received LD-DAC at 5 mg/m2 for 5 consecutive days. Chimerism monitoring was performed 4 weeks after the treatment. Patients who showed a favorable response were followed-up every 6–8 weeks. For patients who did not achieve a favorable response, the LD-DAC treatment was repeated every 6–8 weeks for up to 4 cycles. For patients undergoing immunosuppressive (IS) treatment, either as prophylaxis or for ongoing GvHD, RWIS was not implemented. For patients not receiving immunosuppressive treatment, no immunomodulatory therapy, such as interferon administration or DLI, were allowed. Patients were removed from the trial in the case of events such as the emergence of MRD, relapse, new onset, or aggravation of existing GvHD to grade III–IV aGvHD or moderate/severe cGvHD, life-threatening infection, SOS, TA-TMA, PRES, or other severe HSCT-associated complication (Figure 1).
Figure 1 Flow chart of the study design.
Definition of Response and Study Endpoints
Responses were assigned as follows: (1) Complete response (CR): patients achieving FDC (≥99%); (2) major response (MR): patients with increased donor chimerism (≥95%); (3) partial response (PR): patients with a 10% increase in the level of donor chimerism but that failed to reach 95%; and (4) no response (NR): patients with no or less than a 10% increase in the level of donor chimerism, and that failed to reach 95%. CRs and MRs were considered favorable, whereas PRs or NRs were considered unfavorable.
The primary endpoint of the study was achieving favorable responses (CR and MR) at 6 months after enrollment. Secondary endpoints included unfavorable events, namely, newly developed grade III–IV aGvHD or moderate to severe cGvHD, graft failure, relapse, or nonrelapse mortality (NRM) documented 6 months after enrollment; and survival data, including overall survival (OS), RR, NRM, and event-free survival (EFS) at 2 years after allo-HSCT.
Chimerism Analysis
Genomic DNA was extracted from 200 μL of CD3+ T cells (EDTA-treated) obtained from whole blood or bone marrow. A total of 25 ng of the extracted DNA was used for the amplification of 16 autosomal STRs (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, D5S818, D13S317, D16S539, D2S1338, D19S433, VWA, D12S391, D18S51, Amel, D6S1043, and FGA) using the AmpFLSTR® Huaxia™ PCR Direct Amplification Kit (Invitrogen, Beijing, China). A total of 0.5 μL of the amplified product was mixed with 9 μL of Hi-Di formamide and 0.5 μL of GeneScan-500 Liz molecular weight marker for electrophoresis run on an ABI 3130 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). GeneMapper1 v3.2.1 was adopted to analyze the genotype of each site based on the length of the DNA fragments and allelic ladders. The chimerism values were calculated from the observed peak areas of the informative markers. The calculation procedure was standardized to obtain reproducible chimerism values. The length of the labeled recipient and donor alleles was determined through the analysis of donor and recipient DNA isolated before transplantation. The allele lengths of all the markers were scored. The relative positions of the donor and recipient alleles of a given marker determined its applicability to the calculation of mosaicism, as described by Nollet et al. (22). Chimerism analysis had a sensitivity of 1% and ≥99% was considered to be FDC.
Sample Size Estimation and Statistical Analysis
This was a phase II study based on Simon's two-stage design (23). The study hypothesis was based on an expected favorable response rate ≥80% with an unacceptable favorable response rate ≤50%. The trial would be stopped early if the number of patients showing a favorable response failed to meet the relevant criteria (Supplementary Table 1).
Concerning safety, severe unfavorable events were defined as detectable MRD or disease relapse, graft failure, NRM of any cause, newly developed or aggravated aGvHD to grade III–IV or moderate to severe cGvHD, life-threatening infections, or other allo-HSCT-associated complications such as SOS, TA-TMA, and PRES. A 30% value was set as the unacceptable level of overall incidence of severe adverse events following, which the study would be stopped early based on the continuous monitoring for toxicity using Pocock-type boundary (Supplementary Table 2) (24). Survival rates were calculated using Kaplan–Meier estimates (25). OS was calculated from day 0 to the date of death from any cause. EFS was calculated from day 0 to the date of occurrence of aGVHD (III–IV) or moderate to severe cGVHD, graft failure, relapse, or death of all causes.
Results
Patient Characteristics
A total of 14 patients were enrolled in the study. All the patients had hematological malignancies and received MAC mostly with fludarabine (150 mg/m2) and busulfan (12.8 mg/kg) or sequential high-dose chemotherapy (cladribine + cytarabine + etoposide) followed by fludarabine (150 mg/m2) and busulfan (9.6 mg/kg) conditioning. For myeloid leukemia, GvHD prophylaxis was a standard regimen comprising cyclosporin plus methotrexate and mycophenolate mofetil, with anti-thymoglobulin (ATG) 6 or 10 mg/kg for HLA-MUD or mismatched related donor transplantation. For patients with lymphoid malignancies, GvHD prophylaxis was post-transplantation cyclophosphamide [50 mg/(kg·day−1) at days +3 and +4] with tacrolimus starting from day+5 or low-dose ATG [2.5 mg/(kg·day−1) at day +15 or after neutrophil engraftment in MUD and haplo settings]. All these patients achieved negative MRD day 28–30 after allo-HSCT and remained negative when enrolled in this study. The characteristics of the patients are shown in Table 1.
Table 1 Patient characteristics and outcomes.
UPN #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 #13 #14
Age 45 20 45 51 20 51 16 40 29 20 60 20 20 16
Sex M M F F M F M M M M M F M M
Diagnosis CML ALL AML MDS-EB2 ALL AML ALL AML Sezary T-NHL AML AML Ph+ ALL ALL
Disease status at transplant CP3- T315I CR1 CR1 NR CR1 CR1 CR1 CR2 NR CR3 MRD+ CR1 MRD+ CR1 CR1 CR1
Donor type Haplo MUD Sib MUD Sib Sib Haplo Sib MUD Haplo Sib MUD Haplo Sib
GvHD status Skin cGvHD / / / / / / / / / / / / /
IS prophylaxis FK506 FK506 / CsA FK506 / / / / FK506 FK506 FK506 FK506 FK506
Time of MC +90 +60 +100 +60 +76 +120 +101 +157 +180 +92 +35 +75 +30 +30
MRD level – – – – – – – – – – – – – –
DC level 89% 97% 82% 76% 89% 93% 91% 89% 93% 92% 81% 91% 59% 85%
DC after the first LD-DAC >99% 95% 89% 94% 81% >99% 95% >99% 96% 95% 93% 97% 2% 98%
DC after the second LD-DAC / >99% >99% 86% 90% / 95% / >99% >99% >99% 99% / /
DC after the third LD-DAC / / / 86% 96% / 2% / / / / / / /
DC level at six-month >99% >99% >99% 86% 96% >99% 2% >99% >99% >99% >99% 99% 0 98%
Six-month response CR CR CR PR MR CR NR CR CR CR CR CR NR MR
GvHD* – – – + – – – – – – + – – –
Relapse** – – – + – – – – – – – – – –
Graft failure*** – – – – – – + – – – – – + –
NRM – – – – – – – – – – + – – –
Inremission + + + + + + + + + + – + + +
OS (days) 878+ 822+ 803+ 709+ 546+ 529+ 509+ 456+ 418+ 287+ 372 321+ 257+ 130+
UPN, unique patient number; CML, chronic myelocytic leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; MDS EB2, myelodysplastic syndrome with excess blasts 2; T-NHL, T cell non-Hodgkin's lymphoma; Ph+, Philadelphia chromosome-positive; CP3, third chronic phase; CR1/2/3, first/second/third complete remission; NR, nonremission; MRD+, measurable residual disease-positive; Haplo, haploidentical; MUD, matched unrelated donor; Sib, sibling; cGvHD, chronic graft versus host disease; IS, immunosuppressor; CsA, cyclosporine A; MC, mixed chimerism; DC, donor chimerism; LD-DAC, low-dose decitabine; CR, complete response; PR, partial response; MR, major response; NR, no response; NRM, nonrelapse mortality; OS, overall survival.
* UPN#4 presented newly developed grade II acute GvHD (skin rash) which progressed to chronic skin GvHD; UPN#11 developed bronchiolitis obliterans (BO) 4 months after the second cycle of LD-DAC and eventually died of a lung infection.
** Relapse: UPN#4 progressed to AML on day +335 and received azacytidine plus venetoclax followed by a second allogeneic hematopoietic stem cell transplantation (allo-HSCT).
*** UPN#7 and UPN#13 both developed graft failure after ganciclovir treatment of CMV DNAemia. UPN#7 subsequently received a second allo-HSCT from a MUD and was in remission 9 months later; UPN#13 underwent a second allo-HSCT from a MUD and was in remission 2months after the second allo-HSCT.
MC was documented from day +30 to day +180 after allo-HSCT, and the donor chimerism level ranged from 59 to 97%. A total of 26 cycles of LD-DAC were given. Five patients received one cycle of LD-DAC, six patients received two, and three received three.
Response to LD-DAC Treatment
A total of 11 patients showed a favorable response (78.6%). Nine of them achieved CR (FDC ≥ 99%)—three after one cycle of LD-DAC, and six after two cycles. Two patients achieved MR (>95% of donor chimerism) after one and three cycles of LD-DAC, respectively. Notably, at 6 months after enrollment or the last follow-up, all of these patients maintained their responses for a median of 372 days (132–780; Figure 2).
Figure 2 Timing and outcome of chimerism analysis among the enrolled patients. Shown is the chimerism outcome for each patient enrolled in the study at different time points. The level of donor chimerism is indicated by the color of the closed circle. The inverted triangle indicates the time of low-dose decitabine (LD-DAC) treatment given for each patient.
Three patients failed to reach a sustainable favorable response. Patient #4 achieved only a PR after two cycles of LD-DAC, with a donor chimerism level of 94%. Patient #7 had a quick MR after the first cycle of LD-DAC but rapidly experienced graft failure after ganciclovir treatment for cytomegalovirus (CMV) reactivation. Patient #13, with 59% donor chimerism, failed to respond and had graft failure 3 weeks after one cycle of LD-DAC (Figure 2).
Overall, 6 months after enrollment, 10 patients maintained a favorable response without major unfavorable events. Four patients had unfavorable events, including relapse with initial PR (patient #4), loss of initial response with graft failure (patient #7), NR with graft failure (patient #13), and development of moderate to severe cGvHD and NRM (patient #11).
Toxicity and Complications
Each adverse event was graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. For the 26 cycles of LD-DAC given, including the two that resulted in graft failure, grade III–IV hematological toxicities were observed, including neutropenia and thrombocytopenia (Table 2). If the two cycles that resulted in graft failure are excluded, the grade IV incidence of neutropenia and thrombocytopenia was 33.3% for both parameters. All the patients recovered rapidly, mostly within 7 days, and no life-threatening neutropenic fever and/or bleeding episodes were observed. No severe nonhematological toxicities were documented.
Table 2 Hematological toxicities after LD-DAC treatment (26 cycles).
WBC (%) ANC (%) Hb (%) PLT (%)
None 0 2 (7.7) 1 (3.8) 1 (3.8)
Grade 1 3 (11.5) 3 (11.5) 8 (30.8) 4 (15.4)
Grade 2 7 (26.9) 5 (19.2) 7 (26.9) 4 (15.4)
Grade 3 6 (23.1) 7 (26.9) 9 (34.6) 8 (30.8)
Grade 4 10 (38.5*) 9 (34.6*) 1 (3.8*) 9 (34.6*)
LD-DAC, low-dose decitabine; WBC, white blood cell count; ANC, absolute neutrophil count; Hb, hemoglobin; PLT, platelet count.
* If the two cycles of treatment that were associated with graft failure are excluded, the grade IV toxicities were 9 (37.5%), 8 (33.3%), 0, and 8 (33.3%) for WBC, ANC, Hb, and PLT, respectively.
There was no aggravation of existing GvHD (patient #1). Patient #4 experienced a new-onset skin rash 4 days after the first LD-DAC treatment, which developed into cGVHD that did not respond well to tacrolimus and was eventually controlled with sirolimus. Patient #11 developed symptoms of dyspnea 4 months after the second LD-DAC treatment and was later diagnosed with bronchiolitis obliterans (BO). Otherwise, there were no life-threatening infections, SOS, TA-TMA, PRES, or other severe complications associated with the HSCT.
Follow-Up Outcome
At the last follow-up on September 30, 2020, the median time of follow-up was 526 days after allo-HSCT (130–878) and 372 days (132–780) after enrollment. A total of 13 patients were alive, including 10 without disease relapse or progression.
Three patients were removed from the study owing to relapse and/or secondary graft failure. Patient #4, who had MDS, progressed to AML 11 months after the first MUD allo-HSCT. The patient was rescued by azacytidine plus venetoclax treatment followed by a second Haplo donor allo-HSCT and was alive and in remission 12 months after the second allo-HSCT. The two patients (#7 and #13) who developed graft failure were rescued following a second allo-HSCT from a MUD and were also alive and in remission nine and 2 months later, respectively. Only patient #11, who developed BO after treatment, died of pulmonary infection (Table 1). Overall, the estimated 2-year OS and EFS after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively (Figure 3).
Figure 3 Kaplan–Meier curve for overall survival (OS) and event-free survival (EFS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) among the enrolled patients. OS, solid line; EFS, dotted line.
Discussion
Various studies have demonstrated that early MC in patients undergoing allo-HSCT with MAC may be suggestive of a relapse. The relapse rate can be as high as 70–90% for patients with reduced donor chimerism, whereas it is only 10–35% for patients with FDC (8–11). In patients with AML/MDS, testing for mixed T lymphocyte chimerism at day +90 to 120 after allo-HSCT is reported to be a promising approach for detecting patients with pending relapse, while preemptive DLI to maintain full donor T cell chimerism may prevent relapse (12). In the setting of acute lymphoblastic leukemia (ALL) after allo-HSCT, based on the comparison of lineage-sorted donor cell chimerism and quantitative PCR analysis of disease-specific genetic rearrangements to detect MRD, Wethmar et al. demonstrated that two measurements were similarly and complementarily effective as indicators of hematological relapse (50 vs. 4%, respectively; p < 0.0001) and decreased OS (47 vs. 87%, respectively; p = 0.004) (26). Terwey et al. also showed that, besides its role in MRD monitoring, MC analysis could additionally provide information for impending relapse. Integrating MRD and chimerism analysis allowed for optimal clinical judgment and decision-making to reduce relapse rates through preemptive interventions (27).
In this study, we focused on a subgroup of patients exhibiting MC of CD3+ T cells either in bone marrow or in peripheral blood, and who were MRD-negative, based on flow cytometry and/or molecular analysis early after allo-HSCT with MAC. In patients presenting with MC, several clinical outcomes can be expected. For instance, some may spontaneously recover to FDC without intervention or remain with stable MC without relapse. An increased loss of donor chimerism with the development of neutropenia or pancytopenia, leading to graft failure, may also occur, while most patients with persistent or increased levels of MC may eventually become MRD-positive and experience disease relapse. To prevent MC-associated relapse and/or graft failure, immune modulation such as RWIS and/or DLI are routinely considered. Based on multivariate analysis, a recent report demonstrated that two consecutive increases in MC in the peripheral blood of patients was a strong indicator for relapse (p < 0.0001) and immunomodulatory strategies such as RWIS or DLI could significantly decrease this relapse rate (15.7 vs. 57.6%, p = 0.0007) (28). Notably, immune modulation is limited in patients with previous grade III–IV aGvHD or with moderate to severe cGvHD. The rate of new-onset GvHD can be as high as ~40%, including grade II–IV aGVHD- or moderate to severe cGVHD. With DLI, GvHD-associated mortality ranges from 4 to 7% (29, 30).
In recent years, HMAs have been shown to exert significant immunomodulatory effects, and clinical studies have been undertaken to assess the usefulness of HMAs for the treatment or prevention of relapse in patients with AML or MDS after allo-HSCT (14, 18–20). In this pilot study, we focused on such a group of patients, who were considered to have the potential for an increased risk of relapse or graft loss, but not necessarily imminent relapse. To rule out the possible effects of other immunomodulatory therapies, RWIS and/or DLI were not implemented in the enrolled patients.
Of the 14 enrolled patients, 11 achieved a FR (9 achieved a CR and 2 a MR) after one to three cycles of LD-DAC treatment. Despite a speedy MR after initial treatment, one patient rapidly experienced secondary graft failure following preemptive therapy for CMV reactivation, while another patient displayed a PR, with skin rash as a cGvHD. Only one patient, who presented with a very low level of donor chimerism (<60%), failed to respond to LD-DAC treatment and rapidly developed secondary graft failure. In terms of safety, the treatment was well tolerated with exerted limited hematological and nonhematological toxicities. More importantly, only two patients developed new symptoms of cGVHD several days or months after the treatment. Most of the patients who achieved and maintained FDC remained alive and in remission without significant clinical complications. Adverse events, including treatment failure, severe GvHD, relapse, and NRM, were documented in only four patients and were acceptable based on continuous monitoring for toxicity using Pocock-type boundary. These data suggested that LD-DAC monotherapy has potential as a treatment option for patients with MC and who are MRD-negative.
There were still questions unanswered regarding to the LD-DAC treatment particularly the influence of diseases (myeloid vs. lymphoid malignancies), donor type (MSD vs. MUD or haplo), GVHD prophylaxis protocol (PTCY vs. CNI-based regimen or ATG vs. no ATG), GVHD status (previous GVHD vs. No GVHD), and the immunosuppressive treatment at LD-DAC treatment (No IS vs. ongoing IS).
The small number of patients enrolled limited the ability to draw definitive conclusions. However, ~80% of the patients responded favorably to LD-DAC treatment with acceptable toxicity, suggesting that LD-DAC may be a potential alternative to RWIS and DLI. Additional prospective studies with larger sample sizes are warranted to confirm the clinical benefits of LD-DAC.
Data Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
The studies involving human participants were reviewed and approved by Ruijin Hospital Ethics Committee, Shanghai Jiao Tong University School of Medicine. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.
Author Contributions
LW, L-nW, JH, and J-lJ conceived and designed the study and acquired, analyzed, and interpreted the data. LW, L-nW, and J-fZ carried out statistical analysis. LW and L-nW prepared the manuscript. LW, L-nW, J-fZ, W-hG, C-hJ, WT, W-lZ, JH, and J-lJ edited and reviewed the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors JH.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.627946/full#supplementary-material
Click here for additional data file. | BUSULFAN, CLADRIBINE, CYCLOSPORINE, CYTARABINE, DECITABINE, ETOPOSIDE, FLUDARABINE PHOSPHATE, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS | DrugsGivenReaction | CC BY | 33708780 | 19,615,855 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Low-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study.
T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m2 daily for 5 days and repeated every 6-8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3-22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.
Introduction
Allogeneic stem cell transplantation (allo-HSCT) is a potentially curative therapy for malignant hematological diseases. Disease relapse remains a major cause of treatment failure (1, 2). The monitoring of disease-related parameters, such as measurable residual disease (MRD), can detect evidence of low-volume disease, which can serve as an indicator for emerging relapse (3). Hematopoietic chimerism analysis, which can distinguish residual recipient hematopoiesis from donor cells, is useful for the monitoring of allograft health and predicting imminent graft rejection, and can also be an indicator of potential relapse (2). The gold standard for quantitative chimerism analysis relies on the polymerase chain reaction (PCR)-based detection of variable number tandem repeats (VNTRs) or short tandem repeat (STR) polymorphisms in DNA from bone marrow or peripheral blood mononucleated cells or T cells, as recommended by the EuroChimerism Consortium (4–7).
Several studies have demonstrated that patients with mixed chimerism (MC) in either mononucleated cells or CD3+ T cells display a significantly higher incidence of relapse (40–90%) than those with complete donor chimerism (10–20%). The time between the detection of MC and relapse (median ~70 days) may permit timely therapeutic intervention (8–10). The rapid withdrawal of immunosuppression (RWIS) and preemptive donor lymphocyte infusion (DLI) may result in full donor chimerism (FDC) and are effective in reducing the relapse rate (RR) (11–14). However, RWIS and DLI have also been associated with complications, such as the development or aggravation of graft-versus-host disease (GvHD). Notably, MC without MRD does not necessarily equate to disease recurrence because the recrudescence of host hematopoiesis may represent normal hematopoiesis. In such a scenario, clinical decisions of immune modulation are complicated owing to the unnecessary risk of aggravation of GvHD (1, 2).
Epigenetic modulation of histone deacetylases (HDCs) such as sirturin-1 or methylation is important in maintaining normal function of hematopoietic stem cells and potentially regulating GvHD or graft versus leukemia effect (GvL) in the allo-HSCT settings (15–17). Hypomethylating agents (HMAs), administered either prophylactically or preemptively, are important treatment options after allo-HSCT for patients with acute myeloid leukemia (AML) or myelodysplasia (MDS) (18, 19). Multiple studies have demonstrated that HMAs exert significant immunomodulatory effects and are important for reducing post-transplantation relapse, and do so without inducing GvHD (20). In our previous study, we observed that low-dose decitabine (LD-DAC) converted MC into FDC in patients during maintenance therapy (21). In this pilot prospective study, we assessed the efficacy and safety of LD-DAC in the treatment of patients with MC in CD3+ T cells after allo-HSCT with myeloablative conditioning (MAC).
Methods
Study Design
This was an investigator-initiated, prospective, nonrandomized, single-arm, phase II clinical trial (NCT 03663751) to evaluate the efficacy and safety of LD-DAC as a monotherapy for patients with MC and who were also MRD-negative after allo-HSCT. The study was approved by the Human Ethics Committee of the Rui Jin Hospital and was conducted in accordance with the Declaration of Helsinki. The study was conducted in the Blood and Marrow Transplantation Center, Department of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. All enrolled patients provided written informed consent.
Study Protocol
The inclusion criteria were as follows: (1) adult patients (16–60) undergoing allo-HSCT with myeloablative conditioning from human leukocyte antigen (HLA)-matched sibling donors (MSDs), matched unrelated donors (MUDs), or haploidentical (Haplo) donors; (2) patients who achieved hematological engraftment and presented with a sustainable absolute neutrophil count (ANC) of >0.5 × 109/L not dependent on granulocyte colony-stimulating factor; (3) patients with hematological malignancies and presenting with measurable disease as indicated by immunophenotyping and/or molecular analysis; and (4) patients presented with MC (<99%) among T cells from either bone marrow or peripheral blood and who were MRD-negative in the bone marrow (<0.01%) after transplantation. The exclusion criteria were (1) patients with grade II-IV acute GvHD (aGvHD) or moderate to severe chronic GVHD (cGvHD) not responding to the treatment and (2) patients with severe complications such as life-threatening infections (bacterial, viral, or fungal), sinusoid obstructive syndrome (SOS), HSCT-associated thrombotic microangiopathy (TA-TMA), or posterior reversible encephalopathy syndrome (PRES) not responding to treatment.
All the enrolled patients received LD-DAC at 5 mg/m2 for 5 consecutive days. Chimerism monitoring was performed 4 weeks after the treatment. Patients who showed a favorable response were followed-up every 6–8 weeks. For patients who did not achieve a favorable response, the LD-DAC treatment was repeated every 6–8 weeks for up to 4 cycles. For patients undergoing immunosuppressive (IS) treatment, either as prophylaxis or for ongoing GvHD, RWIS was not implemented. For patients not receiving immunosuppressive treatment, no immunomodulatory therapy, such as interferon administration or DLI, were allowed. Patients were removed from the trial in the case of events such as the emergence of MRD, relapse, new onset, or aggravation of existing GvHD to grade III–IV aGvHD or moderate/severe cGvHD, life-threatening infection, SOS, TA-TMA, PRES, or other severe HSCT-associated complication (Figure 1).
Figure 1 Flow chart of the study design.
Definition of Response and Study Endpoints
Responses were assigned as follows: (1) Complete response (CR): patients achieving FDC (≥99%); (2) major response (MR): patients with increased donor chimerism (≥95%); (3) partial response (PR): patients with a 10% increase in the level of donor chimerism but that failed to reach 95%; and (4) no response (NR): patients with no or less than a 10% increase in the level of donor chimerism, and that failed to reach 95%. CRs and MRs were considered favorable, whereas PRs or NRs were considered unfavorable.
The primary endpoint of the study was achieving favorable responses (CR and MR) at 6 months after enrollment. Secondary endpoints included unfavorable events, namely, newly developed grade III–IV aGvHD or moderate to severe cGvHD, graft failure, relapse, or nonrelapse mortality (NRM) documented 6 months after enrollment; and survival data, including overall survival (OS), RR, NRM, and event-free survival (EFS) at 2 years after allo-HSCT.
Chimerism Analysis
Genomic DNA was extracted from 200 μL of CD3+ T cells (EDTA-treated) obtained from whole blood or bone marrow. A total of 25 ng of the extracted DNA was used for the amplification of 16 autosomal STRs (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, D5S818, D13S317, D16S539, D2S1338, D19S433, VWA, D12S391, D18S51, Amel, D6S1043, and FGA) using the AmpFLSTR® Huaxia™ PCR Direct Amplification Kit (Invitrogen, Beijing, China). A total of 0.5 μL of the amplified product was mixed with 9 μL of Hi-Di formamide and 0.5 μL of GeneScan-500 Liz molecular weight marker for electrophoresis run on an ABI 3130 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). GeneMapper1 v3.2.1 was adopted to analyze the genotype of each site based on the length of the DNA fragments and allelic ladders. The chimerism values were calculated from the observed peak areas of the informative markers. The calculation procedure was standardized to obtain reproducible chimerism values. The length of the labeled recipient and donor alleles was determined through the analysis of donor and recipient DNA isolated before transplantation. The allele lengths of all the markers were scored. The relative positions of the donor and recipient alleles of a given marker determined its applicability to the calculation of mosaicism, as described by Nollet et al. (22). Chimerism analysis had a sensitivity of 1% and ≥99% was considered to be FDC.
Sample Size Estimation and Statistical Analysis
This was a phase II study based on Simon's two-stage design (23). The study hypothesis was based on an expected favorable response rate ≥80% with an unacceptable favorable response rate ≤50%. The trial would be stopped early if the number of patients showing a favorable response failed to meet the relevant criteria (Supplementary Table 1).
Concerning safety, severe unfavorable events were defined as detectable MRD or disease relapse, graft failure, NRM of any cause, newly developed or aggravated aGvHD to grade III–IV or moderate to severe cGvHD, life-threatening infections, or other allo-HSCT-associated complications such as SOS, TA-TMA, and PRES. A 30% value was set as the unacceptable level of overall incidence of severe adverse events following, which the study would be stopped early based on the continuous monitoring for toxicity using Pocock-type boundary (Supplementary Table 2) (24). Survival rates were calculated using Kaplan–Meier estimates (25). OS was calculated from day 0 to the date of death from any cause. EFS was calculated from day 0 to the date of occurrence of aGVHD (III–IV) or moderate to severe cGVHD, graft failure, relapse, or death of all causes.
Results
Patient Characteristics
A total of 14 patients were enrolled in the study. All the patients had hematological malignancies and received MAC mostly with fludarabine (150 mg/m2) and busulfan (12.8 mg/kg) or sequential high-dose chemotherapy (cladribine + cytarabine + etoposide) followed by fludarabine (150 mg/m2) and busulfan (9.6 mg/kg) conditioning. For myeloid leukemia, GvHD prophylaxis was a standard regimen comprising cyclosporin plus methotrexate and mycophenolate mofetil, with anti-thymoglobulin (ATG) 6 or 10 mg/kg for HLA-MUD or mismatched related donor transplantation. For patients with lymphoid malignancies, GvHD prophylaxis was post-transplantation cyclophosphamide [50 mg/(kg·day−1) at days +3 and +4] with tacrolimus starting from day+5 or low-dose ATG [2.5 mg/(kg·day−1) at day +15 or after neutrophil engraftment in MUD and haplo settings]. All these patients achieved negative MRD day 28–30 after allo-HSCT and remained negative when enrolled in this study. The characteristics of the patients are shown in Table 1.
Table 1 Patient characteristics and outcomes.
UPN #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 #13 #14
Age 45 20 45 51 20 51 16 40 29 20 60 20 20 16
Sex M M F F M F M M M M M F M M
Diagnosis CML ALL AML MDS-EB2 ALL AML ALL AML Sezary T-NHL AML AML Ph+ ALL ALL
Disease status at transplant CP3- T315I CR1 CR1 NR CR1 CR1 CR1 CR2 NR CR3 MRD+ CR1 MRD+ CR1 CR1 CR1
Donor type Haplo MUD Sib MUD Sib Sib Haplo Sib MUD Haplo Sib MUD Haplo Sib
GvHD status Skin cGvHD / / / / / / / / / / / / /
IS prophylaxis FK506 FK506 / CsA FK506 / / / / FK506 FK506 FK506 FK506 FK506
Time of MC +90 +60 +100 +60 +76 +120 +101 +157 +180 +92 +35 +75 +30 +30
MRD level – – – – – – – – – – – – – –
DC level 89% 97% 82% 76% 89% 93% 91% 89% 93% 92% 81% 91% 59% 85%
DC after the first LD-DAC >99% 95% 89% 94% 81% >99% 95% >99% 96% 95% 93% 97% 2% 98%
DC after the second LD-DAC / >99% >99% 86% 90% / 95% / >99% >99% >99% 99% / /
DC after the third LD-DAC / / / 86% 96% / 2% / / / / / / /
DC level at six-month >99% >99% >99% 86% 96% >99% 2% >99% >99% >99% >99% 99% 0 98%
Six-month response CR CR CR PR MR CR NR CR CR CR CR CR NR MR
GvHD* – – – + – – – – – – + – – –
Relapse** – – – + – – – – – – – – – –
Graft failure*** – – – – – – + – – – – – + –
NRM – – – – – – – – – – + – – –
Inremission + + + + + + + + + + – + + +
OS (days) 878+ 822+ 803+ 709+ 546+ 529+ 509+ 456+ 418+ 287+ 372 321+ 257+ 130+
UPN, unique patient number; CML, chronic myelocytic leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; MDS EB2, myelodysplastic syndrome with excess blasts 2; T-NHL, T cell non-Hodgkin's lymphoma; Ph+, Philadelphia chromosome-positive; CP3, third chronic phase; CR1/2/3, first/second/third complete remission; NR, nonremission; MRD+, measurable residual disease-positive; Haplo, haploidentical; MUD, matched unrelated donor; Sib, sibling; cGvHD, chronic graft versus host disease; IS, immunosuppressor; CsA, cyclosporine A; MC, mixed chimerism; DC, donor chimerism; LD-DAC, low-dose decitabine; CR, complete response; PR, partial response; MR, major response; NR, no response; NRM, nonrelapse mortality; OS, overall survival.
* UPN#4 presented newly developed grade II acute GvHD (skin rash) which progressed to chronic skin GvHD; UPN#11 developed bronchiolitis obliterans (BO) 4 months after the second cycle of LD-DAC and eventually died of a lung infection.
** Relapse: UPN#4 progressed to AML on day +335 and received azacytidine plus venetoclax followed by a second allogeneic hematopoietic stem cell transplantation (allo-HSCT).
*** UPN#7 and UPN#13 both developed graft failure after ganciclovir treatment of CMV DNAemia. UPN#7 subsequently received a second allo-HSCT from a MUD and was in remission 9 months later; UPN#13 underwent a second allo-HSCT from a MUD and was in remission 2months after the second allo-HSCT.
MC was documented from day +30 to day +180 after allo-HSCT, and the donor chimerism level ranged from 59 to 97%. A total of 26 cycles of LD-DAC were given. Five patients received one cycle of LD-DAC, six patients received two, and three received three.
Response to LD-DAC Treatment
A total of 11 patients showed a favorable response (78.6%). Nine of them achieved CR (FDC ≥ 99%)—three after one cycle of LD-DAC, and six after two cycles. Two patients achieved MR (>95% of donor chimerism) after one and three cycles of LD-DAC, respectively. Notably, at 6 months after enrollment or the last follow-up, all of these patients maintained their responses for a median of 372 days (132–780; Figure 2).
Figure 2 Timing and outcome of chimerism analysis among the enrolled patients. Shown is the chimerism outcome for each patient enrolled in the study at different time points. The level of donor chimerism is indicated by the color of the closed circle. The inverted triangle indicates the time of low-dose decitabine (LD-DAC) treatment given for each patient.
Three patients failed to reach a sustainable favorable response. Patient #4 achieved only a PR after two cycles of LD-DAC, with a donor chimerism level of 94%. Patient #7 had a quick MR after the first cycle of LD-DAC but rapidly experienced graft failure after ganciclovir treatment for cytomegalovirus (CMV) reactivation. Patient #13, with 59% donor chimerism, failed to respond and had graft failure 3 weeks after one cycle of LD-DAC (Figure 2).
Overall, 6 months after enrollment, 10 patients maintained a favorable response without major unfavorable events. Four patients had unfavorable events, including relapse with initial PR (patient #4), loss of initial response with graft failure (patient #7), NR with graft failure (patient #13), and development of moderate to severe cGvHD and NRM (patient #11).
Toxicity and Complications
Each adverse event was graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. For the 26 cycles of LD-DAC given, including the two that resulted in graft failure, grade III–IV hematological toxicities were observed, including neutropenia and thrombocytopenia (Table 2). If the two cycles that resulted in graft failure are excluded, the grade IV incidence of neutropenia and thrombocytopenia was 33.3% for both parameters. All the patients recovered rapidly, mostly within 7 days, and no life-threatening neutropenic fever and/or bleeding episodes were observed. No severe nonhematological toxicities were documented.
Table 2 Hematological toxicities after LD-DAC treatment (26 cycles).
WBC (%) ANC (%) Hb (%) PLT (%)
None 0 2 (7.7) 1 (3.8) 1 (3.8)
Grade 1 3 (11.5) 3 (11.5) 8 (30.8) 4 (15.4)
Grade 2 7 (26.9) 5 (19.2) 7 (26.9) 4 (15.4)
Grade 3 6 (23.1) 7 (26.9) 9 (34.6) 8 (30.8)
Grade 4 10 (38.5*) 9 (34.6*) 1 (3.8*) 9 (34.6*)
LD-DAC, low-dose decitabine; WBC, white blood cell count; ANC, absolute neutrophil count; Hb, hemoglobin; PLT, platelet count.
* If the two cycles of treatment that were associated with graft failure are excluded, the grade IV toxicities were 9 (37.5%), 8 (33.3%), 0, and 8 (33.3%) for WBC, ANC, Hb, and PLT, respectively.
There was no aggravation of existing GvHD (patient #1). Patient #4 experienced a new-onset skin rash 4 days after the first LD-DAC treatment, which developed into cGVHD that did not respond well to tacrolimus and was eventually controlled with sirolimus. Patient #11 developed symptoms of dyspnea 4 months after the second LD-DAC treatment and was later diagnosed with bronchiolitis obliterans (BO). Otherwise, there were no life-threatening infections, SOS, TA-TMA, PRES, or other severe complications associated with the HSCT.
Follow-Up Outcome
At the last follow-up on September 30, 2020, the median time of follow-up was 526 days after allo-HSCT (130–878) and 372 days (132–780) after enrollment. A total of 13 patients were alive, including 10 without disease relapse or progression.
Three patients were removed from the study owing to relapse and/or secondary graft failure. Patient #4, who had MDS, progressed to AML 11 months after the first MUD allo-HSCT. The patient was rescued by azacytidine plus venetoclax treatment followed by a second Haplo donor allo-HSCT and was alive and in remission 12 months after the second allo-HSCT. The two patients (#7 and #13) who developed graft failure were rescued following a second allo-HSCT from a MUD and were also alive and in remission nine and 2 months later, respectively. Only patient #11, who developed BO after treatment, died of pulmonary infection (Table 1). Overall, the estimated 2-year OS and EFS after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively (Figure 3).
Figure 3 Kaplan–Meier curve for overall survival (OS) and event-free survival (EFS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) among the enrolled patients. OS, solid line; EFS, dotted line.
Discussion
Various studies have demonstrated that early MC in patients undergoing allo-HSCT with MAC may be suggestive of a relapse. The relapse rate can be as high as 70–90% for patients with reduced donor chimerism, whereas it is only 10–35% for patients with FDC (8–11). In patients with AML/MDS, testing for mixed T lymphocyte chimerism at day +90 to 120 after allo-HSCT is reported to be a promising approach for detecting patients with pending relapse, while preemptive DLI to maintain full donor T cell chimerism may prevent relapse (12). In the setting of acute lymphoblastic leukemia (ALL) after allo-HSCT, based on the comparison of lineage-sorted donor cell chimerism and quantitative PCR analysis of disease-specific genetic rearrangements to detect MRD, Wethmar et al. demonstrated that two measurements were similarly and complementarily effective as indicators of hematological relapse (50 vs. 4%, respectively; p < 0.0001) and decreased OS (47 vs. 87%, respectively; p = 0.004) (26). Terwey et al. also showed that, besides its role in MRD monitoring, MC analysis could additionally provide information for impending relapse. Integrating MRD and chimerism analysis allowed for optimal clinical judgment and decision-making to reduce relapse rates through preemptive interventions (27).
In this study, we focused on a subgroup of patients exhibiting MC of CD3+ T cells either in bone marrow or in peripheral blood, and who were MRD-negative, based on flow cytometry and/or molecular analysis early after allo-HSCT with MAC. In patients presenting with MC, several clinical outcomes can be expected. For instance, some may spontaneously recover to FDC without intervention or remain with stable MC without relapse. An increased loss of donor chimerism with the development of neutropenia or pancytopenia, leading to graft failure, may also occur, while most patients with persistent or increased levels of MC may eventually become MRD-positive and experience disease relapse. To prevent MC-associated relapse and/or graft failure, immune modulation such as RWIS and/or DLI are routinely considered. Based on multivariate analysis, a recent report demonstrated that two consecutive increases in MC in the peripheral blood of patients was a strong indicator for relapse (p < 0.0001) and immunomodulatory strategies such as RWIS or DLI could significantly decrease this relapse rate (15.7 vs. 57.6%, p = 0.0007) (28). Notably, immune modulation is limited in patients with previous grade III–IV aGvHD or with moderate to severe cGvHD. The rate of new-onset GvHD can be as high as ~40%, including grade II–IV aGVHD- or moderate to severe cGVHD. With DLI, GvHD-associated mortality ranges from 4 to 7% (29, 30).
In recent years, HMAs have been shown to exert significant immunomodulatory effects, and clinical studies have been undertaken to assess the usefulness of HMAs for the treatment or prevention of relapse in patients with AML or MDS after allo-HSCT (14, 18–20). In this pilot study, we focused on such a group of patients, who were considered to have the potential for an increased risk of relapse or graft loss, but not necessarily imminent relapse. To rule out the possible effects of other immunomodulatory therapies, RWIS and/or DLI were not implemented in the enrolled patients.
Of the 14 enrolled patients, 11 achieved a FR (9 achieved a CR and 2 a MR) after one to three cycles of LD-DAC treatment. Despite a speedy MR after initial treatment, one patient rapidly experienced secondary graft failure following preemptive therapy for CMV reactivation, while another patient displayed a PR, with skin rash as a cGvHD. Only one patient, who presented with a very low level of donor chimerism (<60%), failed to respond to LD-DAC treatment and rapidly developed secondary graft failure. In terms of safety, the treatment was well tolerated with exerted limited hematological and nonhematological toxicities. More importantly, only two patients developed new symptoms of cGVHD several days or months after the treatment. Most of the patients who achieved and maintained FDC remained alive and in remission without significant clinical complications. Adverse events, including treatment failure, severe GvHD, relapse, and NRM, were documented in only four patients and were acceptable based on continuous monitoring for toxicity using Pocock-type boundary. These data suggested that LD-DAC monotherapy has potential as a treatment option for patients with MC and who are MRD-negative.
There were still questions unanswered regarding to the LD-DAC treatment particularly the influence of diseases (myeloid vs. lymphoid malignancies), donor type (MSD vs. MUD or haplo), GVHD prophylaxis protocol (PTCY vs. CNI-based regimen or ATG vs. no ATG), GVHD status (previous GVHD vs. No GVHD), and the immunosuppressive treatment at LD-DAC treatment (No IS vs. ongoing IS).
The small number of patients enrolled limited the ability to draw definitive conclusions. However, ~80% of the patients responded favorably to LD-DAC treatment with acceptable toxicity, suggesting that LD-DAC may be a potential alternative to RWIS and DLI. Additional prospective studies with larger sample sizes are warranted to confirm the clinical benefits of LD-DAC.
Data Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
The studies involving human participants were reviewed and approved by Ruijin Hospital Ethics Committee, Shanghai Jiao Tong University School of Medicine. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.
Author Contributions
LW, L-nW, JH, and J-lJ conceived and designed the study and acquired, analyzed, and interpreted the data. LW, L-nW, and J-fZ carried out statistical analysis. LW and L-nW prepared the manuscript. LW, L-nW, J-fZ, W-hG, C-hJ, WT, W-lZ, JH, and J-lJ edited and reviewed the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors JH.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.627946/full#supplementary-material
Click here for additional data file. | BUSULFAN, CLADRIBINE, CYCLOSPORINE, CYTARABINE, DECITABINE, ETOPOSIDE, FLUDARABINE PHOSPHATE, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS | DrugsGivenReaction | CC BY | 33708780 | 19,615,855 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Low-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study.
T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m2 daily for 5 days and repeated every 6-8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3-22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.
Introduction
Allogeneic stem cell transplantation (allo-HSCT) is a potentially curative therapy for malignant hematological diseases. Disease relapse remains a major cause of treatment failure (1, 2). The monitoring of disease-related parameters, such as measurable residual disease (MRD), can detect evidence of low-volume disease, which can serve as an indicator for emerging relapse (3). Hematopoietic chimerism analysis, which can distinguish residual recipient hematopoiesis from donor cells, is useful for the monitoring of allograft health and predicting imminent graft rejection, and can also be an indicator of potential relapse (2). The gold standard for quantitative chimerism analysis relies on the polymerase chain reaction (PCR)-based detection of variable number tandem repeats (VNTRs) or short tandem repeat (STR) polymorphisms in DNA from bone marrow or peripheral blood mononucleated cells or T cells, as recommended by the EuroChimerism Consortium (4–7).
Several studies have demonstrated that patients with mixed chimerism (MC) in either mononucleated cells or CD3+ T cells display a significantly higher incidence of relapse (40–90%) than those with complete donor chimerism (10–20%). The time between the detection of MC and relapse (median ~70 days) may permit timely therapeutic intervention (8–10). The rapid withdrawal of immunosuppression (RWIS) and preemptive donor lymphocyte infusion (DLI) may result in full donor chimerism (FDC) and are effective in reducing the relapse rate (RR) (11–14). However, RWIS and DLI have also been associated with complications, such as the development or aggravation of graft-versus-host disease (GvHD). Notably, MC without MRD does not necessarily equate to disease recurrence because the recrudescence of host hematopoiesis may represent normal hematopoiesis. In such a scenario, clinical decisions of immune modulation are complicated owing to the unnecessary risk of aggravation of GvHD (1, 2).
Epigenetic modulation of histone deacetylases (HDCs) such as sirturin-1 or methylation is important in maintaining normal function of hematopoietic stem cells and potentially regulating GvHD or graft versus leukemia effect (GvL) in the allo-HSCT settings (15–17). Hypomethylating agents (HMAs), administered either prophylactically or preemptively, are important treatment options after allo-HSCT for patients with acute myeloid leukemia (AML) or myelodysplasia (MDS) (18, 19). Multiple studies have demonstrated that HMAs exert significant immunomodulatory effects and are important for reducing post-transplantation relapse, and do so without inducing GvHD (20). In our previous study, we observed that low-dose decitabine (LD-DAC) converted MC into FDC in patients during maintenance therapy (21). In this pilot prospective study, we assessed the efficacy and safety of LD-DAC in the treatment of patients with MC in CD3+ T cells after allo-HSCT with myeloablative conditioning (MAC).
Methods
Study Design
This was an investigator-initiated, prospective, nonrandomized, single-arm, phase II clinical trial (NCT 03663751) to evaluate the efficacy and safety of LD-DAC as a monotherapy for patients with MC and who were also MRD-negative after allo-HSCT. The study was approved by the Human Ethics Committee of the Rui Jin Hospital and was conducted in accordance with the Declaration of Helsinki. The study was conducted in the Blood and Marrow Transplantation Center, Department of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. All enrolled patients provided written informed consent.
Study Protocol
The inclusion criteria were as follows: (1) adult patients (16–60) undergoing allo-HSCT with myeloablative conditioning from human leukocyte antigen (HLA)-matched sibling donors (MSDs), matched unrelated donors (MUDs), or haploidentical (Haplo) donors; (2) patients who achieved hematological engraftment and presented with a sustainable absolute neutrophil count (ANC) of >0.5 × 109/L not dependent on granulocyte colony-stimulating factor; (3) patients with hematological malignancies and presenting with measurable disease as indicated by immunophenotyping and/or molecular analysis; and (4) patients presented with MC (<99%) among T cells from either bone marrow or peripheral blood and who were MRD-negative in the bone marrow (<0.01%) after transplantation. The exclusion criteria were (1) patients with grade II-IV acute GvHD (aGvHD) or moderate to severe chronic GVHD (cGvHD) not responding to the treatment and (2) patients with severe complications such as life-threatening infections (bacterial, viral, or fungal), sinusoid obstructive syndrome (SOS), HSCT-associated thrombotic microangiopathy (TA-TMA), or posterior reversible encephalopathy syndrome (PRES) not responding to treatment.
All the enrolled patients received LD-DAC at 5 mg/m2 for 5 consecutive days. Chimerism monitoring was performed 4 weeks after the treatment. Patients who showed a favorable response were followed-up every 6–8 weeks. For patients who did not achieve a favorable response, the LD-DAC treatment was repeated every 6–8 weeks for up to 4 cycles. For patients undergoing immunosuppressive (IS) treatment, either as prophylaxis or for ongoing GvHD, RWIS was not implemented. For patients not receiving immunosuppressive treatment, no immunomodulatory therapy, such as interferon administration or DLI, were allowed. Patients were removed from the trial in the case of events such as the emergence of MRD, relapse, new onset, or aggravation of existing GvHD to grade III–IV aGvHD or moderate/severe cGvHD, life-threatening infection, SOS, TA-TMA, PRES, or other severe HSCT-associated complication (Figure 1).
Figure 1 Flow chart of the study design.
Definition of Response and Study Endpoints
Responses were assigned as follows: (1) Complete response (CR): patients achieving FDC (≥99%); (2) major response (MR): patients with increased donor chimerism (≥95%); (3) partial response (PR): patients with a 10% increase in the level of donor chimerism but that failed to reach 95%; and (4) no response (NR): patients with no or less than a 10% increase in the level of donor chimerism, and that failed to reach 95%. CRs and MRs were considered favorable, whereas PRs or NRs were considered unfavorable.
The primary endpoint of the study was achieving favorable responses (CR and MR) at 6 months after enrollment. Secondary endpoints included unfavorable events, namely, newly developed grade III–IV aGvHD or moderate to severe cGvHD, graft failure, relapse, or nonrelapse mortality (NRM) documented 6 months after enrollment; and survival data, including overall survival (OS), RR, NRM, and event-free survival (EFS) at 2 years after allo-HSCT.
Chimerism Analysis
Genomic DNA was extracted from 200 μL of CD3+ T cells (EDTA-treated) obtained from whole blood or bone marrow. A total of 25 ng of the extracted DNA was used for the amplification of 16 autosomal STRs (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, D5S818, D13S317, D16S539, D2S1338, D19S433, VWA, D12S391, D18S51, Amel, D6S1043, and FGA) using the AmpFLSTR® Huaxia™ PCR Direct Amplification Kit (Invitrogen, Beijing, China). A total of 0.5 μL of the amplified product was mixed with 9 μL of Hi-Di formamide and 0.5 μL of GeneScan-500 Liz molecular weight marker for electrophoresis run on an ABI 3130 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). GeneMapper1 v3.2.1 was adopted to analyze the genotype of each site based on the length of the DNA fragments and allelic ladders. The chimerism values were calculated from the observed peak areas of the informative markers. The calculation procedure was standardized to obtain reproducible chimerism values. The length of the labeled recipient and donor alleles was determined through the analysis of donor and recipient DNA isolated before transplantation. The allele lengths of all the markers were scored. The relative positions of the donor and recipient alleles of a given marker determined its applicability to the calculation of mosaicism, as described by Nollet et al. (22). Chimerism analysis had a sensitivity of 1% and ≥99% was considered to be FDC.
Sample Size Estimation and Statistical Analysis
This was a phase II study based on Simon's two-stage design (23). The study hypothesis was based on an expected favorable response rate ≥80% with an unacceptable favorable response rate ≤50%. The trial would be stopped early if the number of patients showing a favorable response failed to meet the relevant criteria (Supplementary Table 1).
Concerning safety, severe unfavorable events were defined as detectable MRD or disease relapse, graft failure, NRM of any cause, newly developed or aggravated aGvHD to grade III–IV or moderate to severe cGvHD, life-threatening infections, or other allo-HSCT-associated complications such as SOS, TA-TMA, and PRES. A 30% value was set as the unacceptable level of overall incidence of severe adverse events following, which the study would be stopped early based on the continuous monitoring for toxicity using Pocock-type boundary (Supplementary Table 2) (24). Survival rates were calculated using Kaplan–Meier estimates (25). OS was calculated from day 0 to the date of death from any cause. EFS was calculated from day 0 to the date of occurrence of aGVHD (III–IV) or moderate to severe cGVHD, graft failure, relapse, or death of all causes.
Results
Patient Characteristics
A total of 14 patients were enrolled in the study. All the patients had hematological malignancies and received MAC mostly with fludarabine (150 mg/m2) and busulfan (12.8 mg/kg) or sequential high-dose chemotherapy (cladribine + cytarabine + etoposide) followed by fludarabine (150 mg/m2) and busulfan (9.6 mg/kg) conditioning. For myeloid leukemia, GvHD prophylaxis was a standard regimen comprising cyclosporin plus methotrexate and mycophenolate mofetil, with anti-thymoglobulin (ATG) 6 or 10 mg/kg for HLA-MUD or mismatched related donor transplantation. For patients with lymphoid malignancies, GvHD prophylaxis was post-transplantation cyclophosphamide [50 mg/(kg·day−1) at days +3 and +4] with tacrolimus starting from day+5 or low-dose ATG [2.5 mg/(kg·day−1) at day +15 or after neutrophil engraftment in MUD and haplo settings]. All these patients achieved negative MRD day 28–30 after allo-HSCT and remained negative when enrolled in this study. The characteristics of the patients are shown in Table 1.
Table 1 Patient characteristics and outcomes.
UPN #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 #13 #14
Age 45 20 45 51 20 51 16 40 29 20 60 20 20 16
Sex M M F F M F M M M M M F M M
Diagnosis CML ALL AML MDS-EB2 ALL AML ALL AML Sezary T-NHL AML AML Ph+ ALL ALL
Disease status at transplant CP3- T315I CR1 CR1 NR CR1 CR1 CR1 CR2 NR CR3 MRD+ CR1 MRD+ CR1 CR1 CR1
Donor type Haplo MUD Sib MUD Sib Sib Haplo Sib MUD Haplo Sib MUD Haplo Sib
GvHD status Skin cGvHD / / / / / / / / / / / / /
IS prophylaxis FK506 FK506 / CsA FK506 / / / / FK506 FK506 FK506 FK506 FK506
Time of MC +90 +60 +100 +60 +76 +120 +101 +157 +180 +92 +35 +75 +30 +30
MRD level – – – – – – – – – – – – – –
DC level 89% 97% 82% 76% 89% 93% 91% 89% 93% 92% 81% 91% 59% 85%
DC after the first LD-DAC >99% 95% 89% 94% 81% >99% 95% >99% 96% 95% 93% 97% 2% 98%
DC after the second LD-DAC / >99% >99% 86% 90% / 95% / >99% >99% >99% 99% / /
DC after the third LD-DAC / / / 86% 96% / 2% / / / / / / /
DC level at six-month >99% >99% >99% 86% 96% >99% 2% >99% >99% >99% >99% 99% 0 98%
Six-month response CR CR CR PR MR CR NR CR CR CR CR CR NR MR
GvHD* – – – + – – – – – – + – – –
Relapse** – – – + – – – – – – – – – –
Graft failure*** – – – – – – + – – – – – + –
NRM – – – – – – – – – – + – – –
Inremission + + + + + + + + + + – + + +
OS (days) 878+ 822+ 803+ 709+ 546+ 529+ 509+ 456+ 418+ 287+ 372 321+ 257+ 130+
UPN, unique patient number; CML, chronic myelocytic leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; MDS EB2, myelodysplastic syndrome with excess blasts 2; T-NHL, T cell non-Hodgkin's lymphoma; Ph+, Philadelphia chromosome-positive; CP3, third chronic phase; CR1/2/3, first/second/third complete remission; NR, nonremission; MRD+, measurable residual disease-positive; Haplo, haploidentical; MUD, matched unrelated donor; Sib, sibling; cGvHD, chronic graft versus host disease; IS, immunosuppressor; CsA, cyclosporine A; MC, mixed chimerism; DC, donor chimerism; LD-DAC, low-dose decitabine; CR, complete response; PR, partial response; MR, major response; NR, no response; NRM, nonrelapse mortality; OS, overall survival.
* UPN#4 presented newly developed grade II acute GvHD (skin rash) which progressed to chronic skin GvHD; UPN#11 developed bronchiolitis obliterans (BO) 4 months after the second cycle of LD-DAC and eventually died of a lung infection.
** Relapse: UPN#4 progressed to AML on day +335 and received azacytidine plus venetoclax followed by a second allogeneic hematopoietic stem cell transplantation (allo-HSCT).
*** UPN#7 and UPN#13 both developed graft failure after ganciclovir treatment of CMV DNAemia. UPN#7 subsequently received a second allo-HSCT from a MUD and was in remission 9 months later; UPN#13 underwent a second allo-HSCT from a MUD and was in remission 2months after the second allo-HSCT.
MC was documented from day +30 to day +180 after allo-HSCT, and the donor chimerism level ranged from 59 to 97%. A total of 26 cycles of LD-DAC were given. Five patients received one cycle of LD-DAC, six patients received two, and three received three.
Response to LD-DAC Treatment
A total of 11 patients showed a favorable response (78.6%). Nine of them achieved CR (FDC ≥ 99%)—three after one cycle of LD-DAC, and six after two cycles. Two patients achieved MR (>95% of donor chimerism) after one and three cycles of LD-DAC, respectively. Notably, at 6 months after enrollment or the last follow-up, all of these patients maintained their responses for a median of 372 days (132–780; Figure 2).
Figure 2 Timing and outcome of chimerism analysis among the enrolled patients. Shown is the chimerism outcome for each patient enrolled in the study at different time points. The level of donor chimerism is indicated by the color of the closed circle. The inverted triangle indicates the time of low-dose decitabine (LD-DAC) treatment given for each patient.
Three patients failed to reach a sustainable favorable response. Patient #4 achieved only a PR after two cycles of LD-DAC, with a donor chimerism level of 94%. Patient #7 had a quick MR after the first cycle of LD-DAC but rapidly experienced graft failure after ganciclovir treatment for cytomegalovirus (CMV) reactivation. Patient #13, with 59% donor chimerism, failed to respond and had graft failure 3 weeks after one cycle of LD-DAC (Figure 2).
Overall, 6 months after enrollment, 10 patients maintained a favorable response without major unfavorable events. Four patients had unfavorable events, including relapse with initial PR (patient #4), loss of initial response with graft failure (patient #7), NR with graft failure (patient #13), and development of moderate to severe cGvHD and NRM (patient #11).
Toxicity and Complications
Each adverse event was graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. For the 26 cycles of LD-DAC given, including the two that resulted in graft failure, grade III–IV hematological toxicities were observed, including neutropenia and thrombocytopenia (Table 2). If the two cycles that resulted in graft failure are excluded, the grade IV incidence of neutropenia and thrombocytopenia was 33.3% for both parameters. All the patients recovered rapidly, mostly within 7 days, and no life-threatening neutropenic fever and/or bleeding episodes were observed. No severe nonhematological toxicities were documented.
Table 2 Hematological toxicities after LD-DAC treatment (26 cycles).
WBC (%) ANC (%) Hb (%) PLT (%)
None 0 2 (7.7) 1 (3.8) 1 (3.8)
Grade 1 3 (11.5) 3 (11.5) 8 (30.8) 4 (15.4)
Grade 2 7 (26.9) 5 (19.2) 7 (26.9) 4 (15.4)
Grade 3 6 (23.1) 7 (26.9) 9 (34.6) 8 (30.8)
Grade 4 10 (38.5*) 9 (34.6*) 1 (3.8*) 9 (34.6*)
LD-DAC, low-dose decitabine; WBC, white blood cell count; ANC, absolute neutrophil count; Hb, hemoglobin; PLT, platelet count.
* If the two cycles of treatment that were associated with graft failure are excluded, the grade IV toxicities were 9 (37.5%), 8 (33.3%), 0, and 8 (33.3%) for WBC, ANC, Hb, and PLT, respectively.
There was no aggravation of existing GvHD (patient #1). Patient #4 experienced a new-onset skin rash 4 days after the first LD-DAC treatment, which developed into cGVHD that did not respond well to tacrolimus and was eventually controlled with sirolimus. Patient #11 developed symptoms of dyspnea 4 months after the second LD-DAC treatment and was later diagnosed with bronchiolitis obliterans (BO). Otherwise, there were no life-threatening infections, SOS, TA-TMA, PRES, or other severe complications associated with the HSCT.
Follow-Up Outcome
At the last follow-up on September 30, 2020, the median time of follow-up was 526 days after allo-HSCT (130–878) and 372 days (132–780) after enrollment. A total of 13 patients were alive, including 10 without disease relapse or progression.
Three patients were removed from the study owing to relapse and/or secondary graft failure. Patient #4, who had MDS, progressed to AML 11 months after the first MUD allo-HSCT. The patient was rescued by azacytidine plus venetoclax treatment followed by a second Haplo donor allo-HSCT and was alive and in remission 12 months after the second allo-HSCT. The two patients (#7 and #13) who developed graft failure were rescued following a second allo-HSCT from a MUD and were also alive and in remission nine and 2 months later, respectively. Only patient #11, who developed BO after treatment, died of pulmonary infection (Table 1). Overall, the estimated 2-year OS and EFS after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively (Figure 3).
Figure 3 Kaplan–Meier curve for overall survival (OS) and event-free survival (EFS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) among the enrolled patients. OS, solid line; EFS, dotted line.
Discussion
Various studies have demonstrated that early MC in patients undergoing allo-HSCT with MAC may be suggestive of a relapse. The relapse rate can be as high as 70–90% for patients with reduced donor chimerism, whereas it is only 10–35% for patients with FDC (8–11). In patients with AML/MDS, testing for mixed T lymphocyte chimerism at day +90 to 120 after allo-HSCT is reported to be a promising approach for detecting patients with pending relapse, while preemptive DLI to maintain full donor T cell chimerism may prevent relapse (12). In the setting of acute lymphoblastic leukemia (ALL) after allo-HSCT, based on the comparison of lineage-sorted donor cell chimerism and quantitative PCR analysis of disease-specific genetic rearrangements to detect MRD, Wethmar et al. demonstrated that two measurements were similarly and complementarily effective as indicators of hematological relapse (50 vs. 4%, respectively; p < 0.0001) and decreased OS (47 vs. 87%, respectively; p = 0.004) (26). Terwey et al. also showed that, besides its role in MRD monitoring, MC analysis could additionally provide information for impending relapse. Integrating MRD and chimerism analysis allowed for optimal clinical judgment and decision-making to reduce relapse rates through preemptive interventions (27).
In this study, we focused on a subgroup of patients exhibiting MC of CD3+ T cells either in bone marrow or in peripheral blood, and who were MRD-negative, based on flow cytometry and/or molecular analysis early after allo-HSCT with MAC. In patients presenting with MC, several clinical outcomes can be expected. For instance, some may spontaneously recover to FDC without intervention or remain with stable MC without relapse. An increased loss of donor chimerism with the development of neutropenia or pancytopenia, leading to graft failure, may also occur, while most patients with persistent or increased levels of MC may eventually become MRD-positive and experience disease relapse. To prevent MC-associated relapse and/or graft failure, immune modulation such as RWIS and/or DLI are routinely considered. Based on multivariate analysis, a recent report demonstrated that two consecutive increases in MC in the peripheral blood of patients was a strong indicator for relapse (p < 0.0001) and immunomodulatory strategies such as RWIS or DLI could significantly decrease this relapse rate (15.7 vs. 57.6%, p = 0.0007) (28). Notably, immune modulation is limited in patients with previous grade III–IV aGvHD or with moderate to severe cGvHD. The rate of new-onset GvHD can be as high as ~40%, including grade II–IV aGVHD- or moderate to severe cGVHD. With DLI, GvHD-associated mortality ranges from 4 to 7% (29, 30).
In recent years, HMAs have been shown to exert significant immunomodulatory effects, and clinical studies have been undertaken to assess the usefulness of HMAs for the treatment or prevention of relapse in patients with AML or MDS after allo-HSCT (14, 18–20). In this pilot study, we focused on such a group of patients, who were considered to have the potential for an increased risk of relapse or graft loss, but not necessarily imminent relapse. To rule out the possible effects of other immunomodulatory therapies, RWIS and/or DLI were not implemented in the enrolled patients.
Of the 14 enrolled patients, 11 achieved a FR (9 achieved a CR and 2 a MR) after one to three cycles of LD-DAC treatment. Despite a speedy MR after initial treatment, one patient rapidly experienced secondary graft failure following preemptive therapy for CMV reactivation, while another patient displayed a PR, with skin rash as a cGvHD. Only one patient, who presented with a very low level of donor chimerism (<60%), failed to respond to LD-DAC treatment and rapidly developed secondary graft failure. In terms of safety, the treatment was well tolerated with exerted limited hematological and nonhematological toxicities. More importantly, only two patients developed new symptoms of cGVHD several days or months after the treatment. Most of the patients who achieved and maintained FDC remained alive and in remission without significant clinical complications. Adverse events, including treatment failure, severe GvHD, relapse, and NRM, were documented in only four patients and were acceptable based on continuous monitoring for toxicity using Pocock-type boundary. These data suggested that LD-DAC monotherapy has potential as a treatment option for patients with MC and who are MRD-negative.
There were still questions unanswered regarding to the LD-DAC treatment particularly the influence of diseases (myeloid vs. lymphoid malignancies), donor type (MSD vs. MUD or haplo), GVHD prophylaxis protocol (PTCY vs. CNI-based regimen or ATG vs. no ATG), GVHD status (previous GVHD vs. No GVHD), and the immunosuppressive treatment at LD-DAC treatment (No IS vs. ongoing IS).
The small number of patients enrolled limited the ability to draw definitive conclusions. However, ~80% of the patients responded favorably to LD-DAC treatment with acceptable toxicity, suggesting that LD-DAC may be a potential alternative to RWIS and DLI. Additional prospective studies with larger sample sizes are warranted to confirm the clinical benefits of LD-DAC.
Data Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
The studies involving human participants were reviewed and approved by Ruijin Hospital Ethics Committee, Shanghai Jiao Tong University School of Medicine. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.
Author Contributions
LW, L-nW, JH, and J-lJ conceived and designed the study and acquired, analyzed, and interpreted the data. LW, L-nW, and J-fZ carried out statistical analysis. LW and L-nW prepared the manuscript. LW, L-nW, J-fZ, W-hG, C-hJ, WT, W-lZ, JH, and J-lJ edited and reviewed the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors JH.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.627946/full#supplementary-material
Click here for additional data file. | BUSULFAN, CLADRIBINE, CYCLOSPORINE, CYTARABINE, DECITABINE, ETOPOSIDE, FLUDARABINE PHOSPHATE, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS | DrugsGivenReaction | CC BY | 33708780 | 19,615,855 | 2021 |
What was the dosage of drug 'BUSULFAN'? | Low-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study.
T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m2 daily for 5 days and repeated every 6-8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3-22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.
Introduction
Allogeneic stem cell transplantation (allo-HSCT) is a potentially curative therapy for malignant hematological diseases. Disease relapse remains a major cause of treatment failure (1, 2). The monitoring of disease-related parameters, such as measurable residual disease (MRD), can detect evidence of low-volume disease, which can serve as an indicator for emerging relapse (3). Hematopoietic chimerism analysis, which can distinguish residual recipient hematopoiesis from donor cells, is useful for the monitoring of allograft health and predicting imminent graft rejection, and can also be an indicator of potential relapse (2). The gold standard for quantitative chimerism analysis relies on the polymerase chain reaction (PCR)-based detection of variable number tandem repeats (VNTRs) or short tandem repeat (STR) polymorphisms in DNA from bone marrow or peripheral blood mononucleated cells or T cells, as recommended by the EuroChimerism Consortium (4–7).
Several studies have demonstrated that patients with mixed chimerism (MC) in either mononucleated cells or CD3+ T cells display a significantly higher incidence of relapse (40–90%) than those with complete donor chimerism (10–20%). The time between the detection of MC and relapse (median ~70 days) may permit timely therapeutic intervention (8–10). The rapid withdrawal of immunosuppression (RWIS) and preemptive donor lymphocyte infusion (DLI) may result in full donor chimerism (FDC) and are effective in reducing the relapse rate (RR) (11–14). However, RWIS and DLI have also been associated with complications, such as the development or aggravation of graft-versus-host disease (GvHD). Notably, MC without MRD does not necessarily equate to disease recurrence because the recrudescence of host hematopoiesis may represent normal hematopoiesis. In such a scenario, clinical decisions of immune modulation are complicated owing to the unnecessary risk of aggravation of GvHD (1, 2).
Epigenetic modulation of histone deacetylases (HDCs) such as sirturin-1 or methylation is important in maintaining normal function of hematopoietic stem cells and potentially regulating GvHD or graft versus leukemia effect (GvL) in the allo-HSCT settings (15–17). Hypomethylating agents (HMAs), administered either prophylactically or preemptively, are important treatment options after allo-HSCT for patients with acute myeloid leukemia (AML) or myelodysplasia (MDS) (18, 19). Multiple studies have demonstrated that HMAs exert significant immunomodulatory effects and are important for reducing post-transplantation relapse, and do so without inducing GvHD (20). In our previous study, we observed that low-dose decitabine (LD-DAC) converted MC into FDC in patients during maintenance therapy (21). In this pilot prospective study, we assessed the efficacy and safety of LD-DAC in the treatment of patients with MC in CD3+ T cells after allo-HSCT with myeloablative conditioning (MAC).
Methods
Study Design
This was an investigator-initiated, prospective, nonrandomized, single-arm, phase II clinical trial (NCT 03663751) to evaluate the efficacy and safety of LD-DAC as a monotherapy for patients with MC and who were also MRD-negative after allo-HSCT. The study was approved by the Human Ethics Committee of the Rui Jin Hospital and was conducted in accordance with the Declaration of Helsinki. The study was conducted in the Blood and Marrow Transplantation Center, Department of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. All enrolled patients provided written informed consent.
Study Protocol
The inclusion criteria were as follows: (1) adult patients (16–60) undergoing allo-HSCT with myeloablative conditioning from human leukocyte antigen (HLA)-matched sibling donors (MSDs), matched unrelated donors (MUDs), or haploidentical (Haplo) donors; (2) patients who achieved hematological engraftment and presented with a sustainable absolute neutrophil count (ANC) of >0.5 × 109/L not dependent on granulocyte colony-stimulating factor; (3) patients with hematological malignancies and presenting with measurable disease as indicated by immunophenotyping and/or molecular analysis; and (4) patients presented with MC (<99%) among T cells from either bone marrow or peripheral blood and who were MRD-negative in the bone marrow (<0.01%) after transplantation. The exclusion criteria were (1) patients with grade II-IV acute GvHD (aGvHD) or moderate to severe chronic GVHD (cGvHD) not responding to the treatment and (2) patients with severe complications such as life-threatening infections (bacterial, viral, or fungal), sinusoid obstructive syndrome (SOS), HSCT-associated thrombotic microangiopathy (TA-TMA), or posterior reversible encephalopathy syndrome (PRES) not responding to treatment.
All the enrolled patients received LD-DAC at 5 mg/m2 for 5 consecutive days. Chimerism monitoring was performed 4 weeks after the treatment. Patients who showed a favorable response were followed-up every 6–8 weeks. For patients who did not achieve a favorable response, the LD-DAC treatment was repeated every 6–8 weeks for up to 4 cycles. For patients undergoing immunosuppressive (IS) treatment, either as prophylaxis or for ongoing GvHD, RWIS was not implemented. For patients not receiving immunosuppressive treatment, no immunomodulatory therapy, such as interferon administration or DLI, were allowed. Patients were removed from the trial in the case of events such as the emergence of MRD, relapse, new onset, or aggravation of existing GvHD to grade III–IV aGvHD or moderate/severe cGvHD, life-threatening infection, SOS, TA-TMA, PRES, or other severe HSCT-associated complication (Figure 1).
Figure 1 Flow chart of the study design.
Definition of Response and Study Endpoints
Responses were assigned as follows: (1) Complete response (CR): patients achieving FDC (≥99%); (2) major response (MR): patients with increased donor chimerism (≥95%); (3) partial response (PR): patients with a 10% increase in the level of donor chimerism but that failed to reach 95%; and (4) no response (NR): patients with no or less than a 10% increase in the level of donor chimerism, and that failed to reach 95%. CRs and MRs were considered favorable, whereas PRs or NRs were considered unfavorable.
The primary endpoint of the study was achieving favorable responses (CR and MR) at 6 months after enrollment. Secondary endpoints included unfavorable events, namely, newly developed grade III–IV aGvHD or moderate to severe cGvHD, graft failure, relapse, or nonrelapse mortality (NRM) documented 6 months after enrollment; and survival data, including overall survival (OS), RR, NRM, and event-free survival (EFS) at 2 years after allo-HSCT.
Chimerism Analysis
Genomic DNA was extracted from 200 μL of CD3+ T cells (EDTA-treated) obtained from whole blood or bone marrow. A total of 25 ng of the extracted DNA was used for the amplification of 16 autosomal STRs (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, D5S818, D13S317, D16S539, D2S1338, D19S433, VWA, D12S391, D18S51, Amel, D6S1043, and FGA) using the AmpFLSTR® Huaxia™ PCR Direct Amplification Kit (Invitrogen, Beijing, China). A total of 0.5 μL of the amplified product was mixed with 9 μL of Hi-Di formamide and 0.5 μL of GeneScan-500 Liz molecular weight marker for electrophoresis run on an ABI 3130 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). GeneMapper1 v3.2.1 was adopted to analyze the genotype of each site based on the length of the DNA fragments and allelic ladders. The chimerism values were calculated from the observed peak areas of the informative markers. The calculation procedure was standardized to obtain reproducible chimerism values. The length of the labeled recipient and donor alleles was determined through the analysis of donor and recipient DNA isolated before transplantation. The allele lengths of all the markers were scored. The relative positions of the donor and recipient alleles of a given marker determined its applicability to the calculation of mosaicism, as described by Nollet et al. (22). Chimerism analysis had a sensitivity of 1% and ≥99% was considered to be FDC.
Sample Size Estimation and Statistical Analysis
This was a phase II study based on Simon's two-stage design (23). The study hypothesis was based on an expected favorable response rate ≥80% with an unacceptable favorable response rate ≤50%. The trial would be stopped early if the number of patients showing a favorable response failed to meet the relevant criteria (Supplementary Table 1).
Concerning safety, severe unfavorable events were defined as detectable MRD or disease relapse, graft failure, NRM of any cause, newly developed or aggravated aGvHD to grade III–IV or moderate to severe cGvHD, life-threatening infections, or other allo-HSCT-associated complications such as SOS, TA-TMA, and PRES. A 30% value was set as the unacceptable level of overall incidence of severe adverse events following, which the study would be stopped early based on the continuous monitoring for toxicity using Pocock-type boundary (Supplementary Table 2) (24). Survival rates were calculated using Kaplan–Meier estimates (25). OS was calculated from day 0 to the date of death from any cause. EFS was calculated from day 0 to the date of occurrence of aGVHD (III–IV) or moderate to severe cGVHD, graft failure, relapse, or death of all causes.
Results
Patient Characteristics
A total of 14 patients were enrolled in the study. All the patients had hematological malignancies and received MAC mostly with fludarabine (150 mg/m2) and busulfan (12.8 mg/kg) or sequential high-dose chemotherapy (cladribine + cytarabine + etoposide) followed by fludarabine (150 mg/m2) and busulfan (9.6 mg/kg) conditioning. For myeloid leukemia, GvHD prophylaxis was a standard regimen comprising cyclosporin plus methotrexate and mycophenolate mofetil, with anti-thymoglobulin (ATG) 6 or 10 mg/kg for HLA-MUD or mismatched related donor transplantation. For patients with lymphoid malignancies, GvHD prophylaxis was post-transplantation cyclophosphamide [50 mg/(kg·day−1) at days +3 and +4] with tacrolimus starting from day+5 or low-dose ATG [2.5 mg/(kg·day−1) at day +15 or after neutrophil engraftment in MUD and haplo settings]. All these patients achieved negative MRD day 28–30 after allo-HSCT and remained negative when enrolled in this study. The characteristics of the patients are shown in Table 1.
Table 1 Patient characteristics and outcomes.
UPN #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 #13 #14
Age 45 20 45 51 20 51 16 40 29 20 60 20 20 16
Sex M M F F M F M M M M M F M M
Diagnosis CML ALL AML MDS-EB2 ALL AML ALL AML Sezary T-NHL AML AML Ph+ ALL ALL
Disease status at transplant CP3- T315I CR1 CR1 NR CR1 CR1 CR1 CR2 NR CR3 MRD+ CR1 MRD+ CR1 CR1 CR1
Donor type Haplo MUD Sib MUD Sib Sib Haplo Sib MUD Haplo Sib MUD Haplo Sib
GvHD status Skin cGvHD / / / / / / / / / / / / /
IS prophylaxis FK506 FK506 / CsA FK506 / / / / FK506 FK506 FK506 FK506 FK506
Time of MC +90 +60 +100 +60 +76 +120 +101 +157 +180 +92 +35 +75 +30 +30
MRD level – – – – – – – – – – – – – –
DC level 89% 97% 82% 76% 89% 93% 91% 89% 93% 92% 81% 91% 59% 85%
DC after the first LD-DAC >99% 95% 89% 94% 81% >99% 95% >99% 96% 95% 93% 97% 2% 98%
DC after the second LD-DAC / >99% >99% 86% 90% / 95% / >99% >99% >99% 99% / /
DC after the third LD-DAC / / / 86% 96% / 2% / / / / / / /
DC level at six-month >99% >99% >99% 86% 96% >99% 2% >99% >99% >99% >99% 99% 0 98%
Six-month response CR CR CR PR MR CR NR CR CR CR CR CR NR MR
GvHD* – – – + – – – – – – + – – –
Relapse** – – – + – – – – – – – – – –
Graft failure*** – – – – – – + – – – – – + –
NRM – – – – – – – – – – + – – –
Inremission + + + + + + + + + + – + + +
OS (days) 878+ 822+ 803+ 709+ 546+ 529+ 509+ 456+ 418+ 287+ 372 321+ 257+ 130+
UPN, unique patient number; CML, chronic myelocytic leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; MDS EB2, myelodysplastic syndrome with excess blasts 2; T-NHL, T cell non-Hodgkin's lymphoma; Ph+, Philadelphia chromosome-positive; CP3, third chronic phase; CR1/2/3, first/second/third complete remission; NR, nonremission; MRD+, measurable residual disease-positive; Haplo, haploidentical; MUD, matched unrelated donor; Sib, sibling; cGvHD, chronic graft versus host disease; IS, immunosuppressor; CsA, cyclosporine A; MC, mixed chimerism; DC, donor chimerism; LD-DAC, low-dose decitabine; CR, complete response; PR, partial response; MR, major response; NR, no response; NRM, nonrelapse mortality; OS, overall survival.
* UPN#4 presented newly developed grade II acute GvHD (skin rash) which progressed to chronic skin GvHD; UPN#11 developed bronchiolitis obliterans (BO) 4 months after the second cycle of LD-DAC and eventually died of a lung infection.
** Relapse: UPN#4 progressed to AML on day +335 and received azacytidine plus venetoclax followed by a second allogeneic hematopoietic stem cell transplantation (allo-HSCT).
*** UPN#7 and UPN#13 both developed graft failure after ganciclovir treatment of CMV DNAemia. UPN#7 subsequently received a second allo-HSCT from a MUD and was in remission 9 months later; UPN#13 underwent a second allo-HSCT from a MUD and was in remission 2months after the second allo-HSCT.
MC was documented from day +30 to day +180 after allo-HSCT, and the donor chimerism level ranged from 59 to 97%. A total of 26 cycles of LD-DAC were given. Five patients received one cycle of LD-DAC, six patients received two, and three received three.
Response to LD-DAC Treatment
A total of 11 patients showed a favorable response (78.6%). Nine of them achieved CR (FDC ≥ 99%)—three after one cycle of LD-DAC, and six after two cycles. Two patients achieved MR (>95% of donor chimerism) after one and three cycles of LD-DAC, respectively. Notably, at 6 months after enrollment or the last follow-up, all of these patients maintained their responses for a median of 372 days (132–780; Figure 2).
Figure 2 Timing and outcome of chimerism analysis among the enrolled patients. Shown is the chimerism outcome for each patient enrolled in the study at different time points. The level of donor chimerism is indicated by the color of the closed circle. The inverted triangle indicates the time of low-dose decitabine (LD-DAC) treatment given for each patient.
Three patients failed to reach a sustainable favorable response. Patient #4 achieved only a PR after two cycles of LD-DAC, with a donor chimerism level of 94%. Patient #7 had a quick MR after the first cycle of LD-DAC but rapidly experienced graft failure after ganciclovir treatment for cytomegalovirus (CMV) reactivation. Patient #13, with 59% donor chimerism, failed to respond and had graft failure 3 weeks after one cycle of LD-DAC (Figure 2).
Overall, 6 months after enrollment, 10 patients maintained a favorable response without major unfavorable events. Four patients had unfavorable events, including relapse with initial PR (patient #4), loss of initial response with graft failure (patient #7), NR with graft failure (patient #13), and development of moderate to severe cGvHD and NRM (patient #11).
Toxicity and Complications
Each adverse event was graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. For the 26 cycles of LD-DAC given, including the two that resulted in graft failure, grade III–IV hematological toxicities were observed, including neutropenia and thrombocytopenia (Table 2). If the two cycles that resulted in graft failure are excluded, the grade IV incidence of neutropenia and thrombocytopenia was 33.3% for both parameters. All the patients recovered rapidly, mostly within 7 days, and no life-threatening neutropenic fever and/or bleeding episodes were observed. No severe nonhematological toxicities were documented.
Table 2 Hematological toxicities after LD-DAC treatment (26 cycles).
WBC (%) ANC (%) Hb (%) PLT (%)
None 0 2 (7.7) 1 (3.8) 1 (3.8)
Grade 1 3 (11.5) 3 (11.5) 8 (30.8) 4 (15.4)
Grade 2 7 (26.9) 5 (19.2) 7 (26.9) 4 (15.4)
Grade 3 6 (23.1) 7 (26.9) 9 (34.6) 8 (30.8)
Grade 4 10 (38.5*) 9 (34.6*) 1 (3.8*) 9 (34.6*)
LD-DAC, low-dose decitabine; WBC, white blood cell count; ANC, absolute neutrophil count; Hb, hemoglobin; PLT, platelet count.
* If the two cycles of treatment that were associated with graft failure are excluded, the grade IV toxicities were 9 (37.5%), 8 (33.3%), 0, and 8 (33.3%) for WBC, ANC, Hb, and PLT, respectively.
There was no aggravation of existing GvHD (patient #1). Patient #4 experienced a new-onset skin rash 4 days after the first LD-DAC treatment, which developed into cGVHD that did not respond well to tacrolimus and was eventually controlled with sirolimus. Patient #11 developed symptoms of dyspnea 4 months after the second LD-DAC treatment and was later diagnosed with bronchiolitis obliterans (BO). Otherwise, there were no life-threatening infections, SOS, TA-TMA, PRES, or other severe complications associated with the HSCT.
Follow-Up Outcome
At the last follow-up on September 30, 2020, the median time of follow-up was 526 days after allo-HSCT (130–878) and 372 days (132–780) after enrollment. A total of 13 patients were alive, including 10 without disease relapse or progression.
Three patients were removed from the study owing to relapse and/or secondary graft failure. Patient #4, who had MDS, progressed to AML 11 months after the first MUD allo-HSCT. The patient was rescued by azacytidine plus venetoclax treatment followed by a second Haplo donor allo-HSCT and was alive and in remission 12 months after the second allo-HSCT. The two patients (#7 and #13) who developed graft failure were rescued following a second allo-HSCT from a MUD and were also alive and in remission nine and 2 months later, respectively. Only patient #11, who developed BO after treatment, died of pulmonary infection (Table 1). Overall, the estimated 2-year OS and EFS after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively (Figure 3).
Figure 3 Kaplan–Meier curve for overall survival (OS) and event-free survival (EFS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) among the enrolled patients. OS, solid line; EFS, dotted line.
Discussion
Various studies have demonstrated that early MC in patients undergoing allo-HSCT with MAC may be suggestive of a relapse. The relapse rate can be as high as 70–90% for patients with reduced donor chimerism, whereas it is only 10–35% for patients with FDC (8–11). In patients with AML/MDS, testing for mixed T lymphocyte chimerism at day +90 to 120 after allo-HSCT is reported to be a promising approach for detecting patients with pending relapse, while preemptive DLI to maintain full donor T cell chimerism may prevent relapse (12). In the setting of acute lymphoblastic leukemia (ALL) after allo-HSCT, based on the comparison of lineage-sorted donor cell chimerism and quantitative PCR analysis of disease-specific genetic rearrangements to detect MRD, Wethmar et al. demonstrated that two measurements were similarly and complementarily effective as indicators of hematological relapse (50 vs. 4%, respectively; p < 0.0001) and decreased OS (47 vs. 87%, respectively; p = 0.004) (26). Terwey et al. also showed that, besides its role in MRD monitoring, MC analysis could additionally provide information for impending relapse. Integrating MRD and chimerism analysis allowed for optimal clinical judgment and decision-making to reduce relapse rates through preemptive interventions (27).
In this study, we focused on a subgroup of patients exhibiting MC of CD3+ T cells either in bone marrow or in peripheral blood, and who were MRD-negative, based on flow cytometry and/or molecular analysis early after allo-HSCT with MAC. In patients presenting with MC, several clinical outcomes can be expected. For instance, some may spontaneously recover to FDC without intervention or remain with stable MC without relapse. An increased loss of donor chimerism with the development of neutropenia or pancytopenia, leading to graft failure, may also occur, while most patients with persistent or increased levels of MC may eventually become MRD-positive and experience disease relapse. To prevent MC-associated relapse and/or graft failure, immune modulation such as RWIS and/or DLI are routinely considered. Based on multivariate analysis, a recent report demonstrated that two consecutive increases in MC in the peripheral blood of patients was a strong indicator for relapse (p < 0.0001) and immunomodulatory strategies such as RWIS or DLI could significantly decrease this relapse rate (15.7 vs. 57.6%, p = 0.0007) (28). Notably, immune modulation is limited in patients with previous grade III–IV aGvHD or with moderate to severe cGvHD. The rate of new-onset GvHD can be as high as ~40%, including grade II–IV aGVHD- or moderate to severe cGVHD. With DLI, GvHD-associated mortality ranges from 4 to 7% (29, 30).
In recent years, HMAs have been shown to exert significant immunomodulatory effects, and clinical studies have been undertaken to assess the usefulness of HMAs for the treatment or prevention of relapse in patients with AML or MDS after allo-HSCT (14, 18–20). In this pilot study, we focused on such a group of patients, who were considered to have the potential for an increased risk of relapse or graft loss, but not necessarily imminent relapse. To rule out the possible effects of other immunomodulatory therapies, RWIS and/or DLI were not implemented in the enrolled patients.
Of the 14 enrolled patients, 11 achieved a FR (9 achieved a CR and 2 a MR) after one to three cycles of LD-DAC treatment. Despite a speedy MR after initial treatment, one patient rapidly experienced secondary graft failure following preemptive therapy for CMV reactivation, while another patient displayed a PR, with skin rash as a cGvHD. Only one patient, who presented with a very low level of donor chimerism (<60%), failed to respond to LD-DAC treatment and rapidly developed secondary graft failure. In terms of safety, the treatment was well tolerated with exerted limited hematological and nonhematological toxicities. More importantly, only two patients developed new symptoms of cGVHD several days or months after the treatment. Most of the patients who achieved and maintained FDC remained alive and in remission without significant clinical complications. Adverse events, including treatment failure, severe GvHD, relapse, and NRM, were documented in only four patients and were acceptable based on continuous monitoring for toxicity using Pocock-type boundary. These data suggested that LD-DAC monotherapy has potential as a treatment option for patients with MC and who are MRD-negative.
There were still questions unanswered regarding to the LD-DAC treatment particularly the influence of diseases (myeloid vs. lymphoid malignancies), donor type (MSD vs. MUD or haplo), GVHD prophylaxis protocol (PTCY vs. CNI-based regimen or ATG vs. no ATG), GVHD status (previous GVHD vs. No GVHD), and the immunosuppressive treatment at LD-DAC treatment (No IS vs. ongoing IS).
The small number of patients enrolled limited the ability to draw definitive conclusions. However, ~80% of the patients responded favorably to LD-DAC treatment with acceptable toxicity, suggesting that LD-DAC may be a potential alternative to RWIS and DLI. Additional prospective studies with larger sample sizes are warranted to confirm the clinical benefits of LD-DAC.
Data Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
The studies involving human participants were reviewed and approved by Ruijin Hospital Ethics Committee, Shanghai Jiao Tong University School of Medicine. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.
Author Contributions
LW, L-nW, JH, and J-lJ conceived and designed the study and acquired, analyzed, and interpreted the data. LW, L-nW, and J-fZ carried out statistical analysis. LW and L-nW prepared the manuscript. LW, L-nW, J-fZ, W-hG, C-hJ, WT, W-lZ, JH, and J-lJ edited and reviewed the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors JH.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.627946/full#supplementary-material
Click here for additional data file. | 12.8 MG/KG | DrugDosageText | CC BY | 33708780 | 19,615,855 | 2021 |
What was the dosage of drug 'DECITABINE'? | Low-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study.
T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m2 daily for 5 days and repeated every 6-8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3-22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.
Introduction
Allogeneic stem cell transplantation (allo-HSCT) is a potentially curative therapy for malignant hematological diseases. Disease relapse remains a major cause of treatment failure (1, 2). The monitoring of disease-related parameters, such as measurable residual disease (MRD), can detect evidence of low-volume disease, which can serve as an indicator for emerging relapse (3). Hematopoietic chimerism analysis, which can distinguish residual recipient hematopoiesis from donor cells, is useful for the monitoring of allograft health and predicting imminent graft rejection, and can also be an indicator of potential relapse (2). The gold standard for quantitative chimerism analysis relies on the polymerase chain reaction (PCR)-based detection of variable number tandem repeats (VNTRs) or short tandem repeat (STR) polymorphisms in DNA from bone marrow or peripheral blood mononucleated cells or T cells, as recommended by the EuroChimerism Consortium (4–7).
Several studies have demonstrated that patients with mixed chimerism (MC) in either mononucleated cells or CD3+ T cells display a significantly higher incidence of relapse (40–90%) than those with complete donor chimerism (10–20%). The time between the detection of MC and relapse (median ~70 days) may permit timely therapeutic intervention (8–10). The rapid withdrawal of immunosuppression (RWIS) and preemptive donor lymphocyte infusion (DLI) may result in full donor chimerism (FDC) and are effective in reducing the relapse rate (RR) (11–14). However, RWIS and DLI have also been associated with complications, such as the development or aggravation of graft-versus-host disease (GvHD). Notably, MC without MRD does not necessarily equate to disease recurrence because the recrudescence of host hematopoiesis may represent normal hematopoiesis. In such a scenario, clinical decisions of immune modulation are complicated owing to the unnecessary risk of aggravation of GvHD (1, 2).
Epigenetic modulation of histone deacetylases (HDCs) such as sirturin-1 or methylation is important in maintaining normal function of hematopoietic stem cells and potentially regulating GvHD or graft versus leukemia effect (GvL) in the allo-HSCT settings (15–17). Hypomethylating agents (HMAs), administered either prophylactically or preemptively, are important treatment options after allo-HSCT for patients with acute myeloid leukemia (AML) or myelodysplasia (MDS) (18, 19). Multiple studies have demonstrated that HMAs exert significant immunomodulatory effects and are important for reducing post-transplantation relapse, and do so without inducing GvHD (20). In our previous study, we observed that low-dose decitabine (LD-DAC) converted MC into FDC in patients during maintenance therapy (21). In this pilot prospective study, we assessed the efficacy and safety of LD-DAC in the treatment of patients with MC in CD3+ T cells after allo-HSCT with myeloablative conditioning (MAC).
Methods
Study Design
This was an investigator-initiated, prospective, nonrandomized, single-arm, phase II clinical trial (NCT 03663751) to evaluate the efficacy and safety of LD-DAC as a monotherapy for patients with MC and who were also MRD-negative after allo-HSCT. The study was approved by the Human Ethics Committee of the Rui Jin Hospital and was conducted in accordance with the Declaration of Helsinki. The study was conducted in the Blood and Marrow Transplantation Center, Department of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. All enrolled patients provided written informed consent.
Study Protocol
The inclusion criteria were as follows: (1) adult patients (16–60) undergoing allo-HSCT with myeloablative conditioning from human leukocyte antigen (HLA)-matched sibling donors (MSDs), matched unrelated donors (MUDs), or haploidentical (Haplo) donors; (2) patients who achieved hematological engraftment and presented with a sustainable absolute neutrophil count (ANC) of >0.5 × 109/L not dependent on granulocyte colony-stimulating factor; (3) patients with hematological malignancies and presenting with measurable disease as indicated by immunophenotyping and/or molecular analysis; and (4) patients presented with MC (<99%) among T cells from either bone marrow or peripheral blood and who were MRD-negative in the bone marrow (<0.01%) after transplantation. The exclusion criteria were (1) patients with grade II-IV acute GvHD (aGvHD) or moderate to severe chronic GVHD (cGvHD) not responding to the treatment and (2) patients with severe complications such as life-threatening infections (bacterial, viral, or fungal), sinusoid obstructive syndrome (SOS), HSCT-associated thrombotic microangiopathy (TA-TMA), or posterior reversible encephalopathy syndrome (PRES) not responding to treatment.
All the enrolled patients received LD-DAC at 5 mg/m2 for 5 consecutive days. Chimerism monitoring was performed 4 weeks after the treatment. Patients who showed a favorable response were followed-up every 6–8 weeks. For patients who did not achieve a favorable response, the LD-DAC treatment was repeated every 6–8 weeks for up to 4 cycles. For patients undergoing immunosuppressive (IS) treatment, either as prophylaxis or for ongoing GvHD, RWIS was not implemented. For patients not receiving immunosuppressive treatment, no immunomodulatory therapy, such as interferon administration or DLI, were allowed. Patients were removed from the trial in the case of events such as the emergence of MRD, relapse, new onset, or aggravation of existing GvHD to grade III–IV aGvHD or moderate/severe cGvHD, life-threatening infection, SOS, TA-TMA, PRES, or other severe HSCT-associated complication (Figure 1).
Figure 1 Flow chart of the study design.
Definition of Response and Study Endpoints
Responses were assigned as follows: (1) Complete response (CR): patients achieving FDC (≥99%); (2) major response (MR): patients with increased donor chimerism (≥95%); (3) partial response (PR): patients with a 10% increase in the level of donor chimerism but that failed to reach 95%; and (4) no response (NR): patients with no or less than a 10% increase in the level of donor chimerism, and that failed to reach 95%. CRs and MRs were considered favorable, whereas PRs or NRs were considered unfavorable.
The primary endpoint of the study was achieving favorable responses (CR and MR) at 6 months after enrollment. Secondary endpoints included unfavorable events, namely, newly developed grade III–IV aGvHD or moderate to severe cGvHD, graft failure, relapse, or nonrelapse mortality (NRM) documented 6 months after enrollment; and survival data, including overall survival (OS), RR, NRM, and event-free survival (EFS) at 2 years after allo-HSCT.
Chimerism Analysis
Genomic DNA was extracted from 200 μL of CD3+ T cells (EDTA-treated) obtained from whole blood or bone marrow. A total of 25 ng of the extracted DNA was used for the amplification of 16 autosomal STRs (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, D5S818, D13S317, D16S539, D2S1338, D19S433, VWA, D12S391, D18S51, Amel, D6S1043, and FGA) using the AmpFLSTR® Huaxia™ PCR Direct Amplification Kit (Invitrogen, Beijing, China). A total of 0.5 μL of the amplified product was mixed with 9 μL of Hi-Di formamide and 0.5 μL of GeneScan-500 Liz molecular weight marker for electrophoresis run on an ABI 3130 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). GeneMapper1 v3.2.1 was adopted to analyze the genotype of each site based on the length of the DNA fragments and allelic ladders. The chimerism values were calculated from the observed peak areas of the informative markers. The calculation procedure was standardized to obtain reproducible chimerism values. The length of the labeled recipient and donor alleles was determined through the analysis of donor and recipient DNA isolated before transplantation. The allele lengths of all the markers were scored. The relative positions of the donor and recipient alleles of a given marker determined its applicability to the calculation of mosaicism, as described by Nollet et al. (22). Chimerism analysis had a sensitivity of 1% and ≥99% was considered to be FDC.
Sample Size Estimation and Statistical Analysis
This was a phase II study based on Simon's two-stage design (23). The study hypothesis was based on an expected favorable response rate ≥80% with an unacceptable favorable response rate ≤50%. The trial would be stopped early if the number of patients showing a favorable response failed to meet the relevant criteria (Supplementary Table 1).
Concerning safety, severe unfavorable events were defined as detectable MRD or disease relapse, graft failure, NRM of any cause, newly developed or aggravated aGvHD to grade III–IV or moderate to severe cGvHD, life-threatening infections, or other allo-HSCT-associated complications such as SOS, TA-TMA, and PRES. A 30% value was set as the unacceptable level of overall incidence of severe adverse events following, which the study would be stopped early based on the continuous monitoring for toxicity using Pocock-type boundary (Supplementary Table 2) (24). Survival rates were calculated using Kaplan–Meier estimates (25). OS was calculated from day 0 to the date of death from any cause. EFS was calculated from day 0 to the date of occurrence of aGVHD (III–IV) or moderate to severe cGVHD, graft failure, relapse, or death of all causes.
Results
Patient Characteristics
A total of 14 patients were enrolled in the study. All the patients had hematological malignancies and received MAC mostly with fludarabine (150 mg/m2) and busulfan (12.8 mg/kg) or sequential high-dose chemotherapy (cladribine + cytarabine + etoposide) followed by fludarabine (150 mg/m2) and busulfan (9.6 mg/kg) conditioning. For myeloid leukemia, GvHD prophylaxis was a standard regimen comprising cyclosporin plus methotrexate and mycophenolate mofetil, with anti-thymoglobulin (ATG) 6 or 10 mg/kg for HLA-MUD or mismatched related donor transplantation. For patients with lymphoid malignancies, GvHD prophylaxis was post-transplantation cyclophosphamide [50 mg/(kg·day−1) at days +3 and +4] with tacrolimus starting from day+5 or low-dose ATG [2.5 mg/(kg·day−1) at day +15 or after neutrophil engraftment in MUD and haplo settings]. All these patients achieved negative MRD day 28–30 after allo-HSCT and remained negative when enrolled in this study. The characteristics of the patients are shown in Table 1.
Table 1 Patient characteristics and outcomes.
UPN #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 #13 #14
Age 45 20 45 51 20 51 16 40 29 20 60 20 20 16
Sex M M F F M F M M M M M F M M
Diagnosis CML ALL AML MDS-EB2 ALL AML ALL AML Sezary T-NHL AML AML Ph+ ALL ALL
Disease status at transplant CP3- T315I CR1 CR1 NR CR1 CR1 CR1 CR2 NR CR3 MRD+ CR1 MRD+ CR1 CR1 CR1
Donor type Haplo MUD Sib MUD Sib Sib Haplo Sib MUD Haplo Sib MUD Haplo Sib
GvHD status Skin cGvHD / / / / / / / / / / / / /
IS prophylaxis FK506 FK506 / CsA FK506 / / / / FK506 FK506 FK506 FK506 FK506
Time of MC +90 +60 +100 +60 +76 +120 +101 +157 +180 +92 +35 +75 +30 +30
MRD level – – – – – – – – – – – – – –
DC level 89% 97% 82% 76% 89% 93% 91% 89% 93% 92% 81% 91% 59% 85%
DC after the first LD-DAC >99% 95% 89% 94% 81% >99% 95% >99% 96% 95% 93% 97% 2% 98%
DC after the second LD-DAC / >99% >99% 86% 90% / 95% / >99% >99% >99% 99% / /
DC after the third LD-DAC / / / 86% 96% / 2% / / / / / / /
DC level at six-month >99% >99% >99% 86% 96% >99% 2% >99% >99% >99% >99% 99% 0 98%
Six-month response CR CR CR PR MR CR NR CR CR CR CR CR NR MR
GvHD* – – – + – – – – – – + – – –
Relapse** – – – + – – – – – – – – – –
Graft failure*** – – – – – – + – – – – – + –
NRM – – – – – – – – – – + – – –
Inremission + + + + + + + + + + – + + +
OS (days) 878+ 822+ 803+ 709+ 546+ 529+ 509+ 456+ 418+ 287+ 372 321+ 257+ 130+
UPN, unique patient number; CML, chronic myelocytic leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; MDS EB2, myelodysplastic syndrome with excess blasts 2; T-NHL, T cell non-Hodgkin's lymphoma; Ph+, Philadelphia chromosome-positive; CP3, third chronic phase; CR1/2/3, first/second/third complete remission; NR, nonremission; MRD+, measurable residual disease-positive; Haplo, haploidentical; MUD, matched unrelated donor; Sib, sibling; cGvHD, chronic graft versus host disease; IS, immunosuppressor; CsA, cyclosporine A; MC, mixed chimerism; DC, donor chimerism; LD-DAC, low-dose decitabine; CR, complete response; PR, partial response; MR, major response; NR, no response; NRM, nonrelapse mortality; OS, overall survival.
* UPN#4 presented newly developed grade II acute GvHD (skin rash) which progressed to chronic skin GvHD; UPN#11 developed bronchiolitis obliterans (BO) 4 months after the second cycle of LD-DAC and eventually died of a lung infection.
** Relapse: UPN#4 progressed to AML on day +335 and received azacytidine plus venetoclax followed by a second allogeneic hematopoietic stem cell transplantation (allo-HSCT).
*** UPN#7 and UPN#13 both developed graft failure after ganciclovir treatment of CMV DNAemia. UPN#7 subsequently received a second allo-HSCT from a MUD and was in remission 9 months later; UPN#13 underwent a second allo-HSCT from a MUD and was in remission 2months after the second allo-HSCT.
MC was documented from day +30 to day +180 after allo-HSCT, and the donor chimerism level ranged from 59 to 97%. A total of 26 cycles of LD-DAC were given. Five patients received one cycle of LD-DAC, six patients received two, and three received three.
Response to LD-DAC Treatment
A total of 11 patients showed a favorable response (78.6%). Nine of them achieved CR (FDC ≥ 99%)—three after one cycle of LD-DAC, and six after two cycles. Two patients achieved MR (>95% of donor chimerism) after one and three cycles of LD-DAC, respectively. Notably, at 6 months after enrollment or the last follow-up, all of these patients maintained their responses for a median of 372 days (132–780; Figure 2).
Figure 2 Timing and outcome of chimerism analysis among the enrolled patients. Shown is the chimerism outcome for each patient enrolled in the study at different time points. The level of donor chimerism is indicated by the color of the closed circle. The inverted triangle indicates the time of low-dose decitabine (LD-DAC) treatment given for each patient.
Three patients failed to reach a sustainable favorable response. Patient #4 achieved only a PR after two cycles of LD-DAC, with a donor chimerism level of 94%. Patient #7 had a quick MR after the first cycle of LD-DAC but rapidly experienced graft failure after ganciclovir treatment for cytomegalovirus (CMV) reactivation. Patient #13, with 59% donor chimerism, failed to respond and had graft failure 3 weeks after one cycle of LD-DAC (Figure 2).
Overall, 6 months after enrollment, 10 patients maintained a favorable response without major unfavorable events. Four patients had unfavorable events, including relapse with initial PR (patient #4), loss of initial response with graft failure (patient #7), NR with graft failure (patient #13), and development of moderate to severe cGvHD and NRM (patient #11).
Toxicity and Complications
Each adverse event was graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. For the 26 cycles of LD-DAC given, including the two that resulted in graft failure, grade III–IV hematological toxicities were observed, including neutropenia and thrombocytopenia (Table 2). If the two cycles that resulted in graft failure are excluded, the grade IV incidence of neutropenia and thrombocytopenia was 33.3% for both parameters. All the patients recovered rapidly, mostly within 7 days, and no life-threatening neutropenic fever and/or bleeding episodes were observed. No severe nonhematological toxicities were documented.
Table 2 Hematological toxicities after LD-DAC treatment (26 cycles).
WBC (%) ANC (%) Hb (%) PLT (%)
None 0 2 (7.7) 1 (3.8) 1 (3.8)
Grade 1 3 (11.5) 3 (11.5) 8 (30.8) 4 (15.4)
Grade 2 7 (26.9) 5 (19.2) 7 (26.9) 4 (15.4)
Grade 3 6 (23.1) 7 (26.9) 9 (34.6) 8 (30.8)
Grade 4 10 (38.5*) 9 (34.6*) 1 (3.8*) 9 (34.6*)
LD-DAC, low-dose decitabine; WBC, white blood cell count; ANC, absolute neutrophil count; Hb, hemoglobin; PLT, platelet count.
* If the two cycles of treatment that were associated with graft failure are excluded, the grade IV toxicities were 9 (37.5%), 8 (33.3%), 0, and 8 (33.3%) for WBC, ANC, Hb, and PLT, respectively.
There was no aggravation of existing GvHD (patient #1). Patient #4 experienced a new-onset skin rash 4 days after the first LD-DAC treatment, which developed into cGVHD that did not respond well to tacrolimus and was eventually controlled with sirolimus. Patient #11 developed symptoms of dyspnea 4 months after the second LD-DAC treatment and was later diagnosed with bronchiolitis obliterans (BO). Otherwise, there were no life-threatening infections, SOS, TA-TMA, PRES, or other severe complications associated with the HSCT.
Follow-Up Outcome
At the last follow-up on September 30, 2020, the median time of follow-up was 526 days after allo-HSCT (130–878) and 372 days (132–780) after enrollment. A total of 13 patients were alive, including 10 without disease relapse or progression.
Three patients were removed from the study owing to relapse and/or secondary graft failure. Patient #4, who had MDS, progressed to AML 11 months after the first MUD allo-HSCT. The patient was rescued by azacytidine plus venetoclax treatment followed by a second Haplo donor allo-HSCT and was alive and in remission 12 months after the second allo-HSCT. The two patients (#7 and #13) who developed graft failure were rescued following a second allo-HSCT from a MUD and were also alive and in remission nine and 2 months later, respectively. Only patient #11, who developed BO after treatment, died of pulmonary infection (Table 1). Overall, the estimated 2-year OS and EFS after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively (Figure 3).
Figure 3 Kaplan–Meier curve for overall survival (OS) and event-free survival (EFS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) among the enrolled patients. OS, solid line; EFS, dotted line.
Discussion
Various studies have demonstrated that early MC in patients undergoing allo-HSCT with MAC may be suggestive of a relapse. The relapse rate can be as high as 70–90% for patients with reduced donor chimerism, whereas it is only 10–35% for patients with FDC (8–11). In patients with AML/MDS, testing for mixed T lymphocyte chimerism at day +90 to 120 after allo-HSCT is reported to be a promising approach for detecting patients with pending relapse, while preemptive DLI to maintain full donor T cell chimerism may prevent relapse (12). In the setting of acute lymphoblastic leukemia (ALL) after allo-HSCT, based on the comparison of lineage-sorted donor cell chimerism and quantitative PCR analysis of disease-specific genetic rearrangements to detect MRD, Wethmar et al. demonstrated that two measurements were similarly and complementarily effective as indicators of hematological relapse (50 vs. 4%, respectively; p < 0.0001) and decreased OS (47 vs. 87%, respectively; p = 0.004) (26). Terwey et al. also showed that, besides its role in MRD monitoring, MC analysis could additionally provide information for impending relapse. Integrating MRD and chimerism analysis allowed for optimal clinical judgment and decision-making to reduce relapse rates through preemptive interventions (27).
In this study, we focused on a subgroup of patients exhibiting MC of CD3+ T cells either in bone marrow or in peripheral blood, and who were MRD-negative, based on flow cytometry and/or molecular analysis early after allo-HSCT with MAC. In patients presenting with MC, several clinical outcomes can be expected. For instance, some may spontaneously recover to FDC without intervention or remain with stable MC without relapse. An increased loss of donor chimerism with the development of neutropenia or pancytopenia, leading to graft failure, may also occur, while most patients with persistent or increased levels of MC may eventually become MRD-positive and experience disease relapse. To prevent MC-associated relapse and/or graft failure, immune modulation such as RWIS and/or DLI are routinely considered. Based on multivariate analysis, a recent report demonstrated that two consecutive increases in MC in the peripheral blood of patients was a strong indicator for relapse (p < 0.0001) and immunomodulatory strategies such as RWIS or DLI could significantly decrease this relapse rate (15.7 vs. 57.6%, p = 0.0007) (28). Notably, immune modulation is limited in patients with previous grade III–IV aGvHD or with moderate to severe cGvHD. The rate of new-onset GvHD can be as high as ~40%, including grade II–IV aGVHD- or moderate to severe cGVHD. With DLI, GvHD-associated mortality ranges from 4 to 7% (29, 30).
In recent years, HMAs have been shown to exert significant immunomodulatory effects, and clinical studies have been undertaken to assess the usefulness of HMAs for the treatment or prevention of relapse in patients with AML or MDS after allo-HSCT (14, 18–20). In this pilot study, we focused on such a group of patients, who were considered to have the potential for an increased risk of relapse or graft loss, but not necessarily imminent relapse. To rule out the possible effects of other immunomodulatory therapies, RWIS and/or DLI were not implemented in the enrolled patients.
Of the 14 enrolled patients, 11 achieved a FR (9 achieved a CR and 2 a MR) after one to three cycles of LD-DAC treatment. Despite a speedy MR after initial treatment, one patient rapidly experienced secondary graft failure following preemptive therapy for CMV reactivation, while another patient displayed a PR, with skin rash as a cGvHD. Only one patient, who presented with a very low level of donor chimerism (<60%), failed to respond to LD-DAC treatment and rapidly developed secondary graft failure. In terms of safety, the treatment was well tolerated with exerted limited hematological and nonhematological toxicities. More importantly, only two patients developed new symptoms of cGVHD several days or months after the treatment. Most of the patients who achieved and maintained FDC remained alive and in remission without significant clinical complications. Adverse events, including treatment failure, severe GvHD, relapse, and NRM, were documented in only four patients and were acceptable based on continuous monitoring for toxicity using Pocock-type boundary. These data suggested that LD-DAC monotherapy has potential as a treatment option for patients with MC and who are MRD-negative.
There were still questions unanswered regarding to the LD-DAC treatment particularly the influence of diseases (myeloid vs. lymphoid malignancies), donor type (MSD vs. MUD or haplo), GVHD prophylaxis protocol (PTCY vs. CNI-based regimen or ATG vs. no ATG), GVHD status (previous GVHD vs. No GVHD), and the immunosuppressive treatment at LD-DAC treatment (No IS vs. ongoing IS).
The small number of patients enrolled limited the ability to draw definitive conclusions. However, ~80% of the patients responded favorably to LD-DAC treatment with acceptable toxicity, suggesting that LD-DAC may be a potential alternative to RWIS and DLI. Additional prospective studies with larger sample sizes are warranted to confirm the clinical benefits of LD-DAC.
Data Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
The studies involving human participants were reviewed and approved by Ruijin Hospital Ethics Committee, Shanghai Jiao Tong University School of Medicine. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.
Author Contributions
LW, L-nW, JH, and J-lJ conceived and designed the study and acquired, analyzed, and interpreted the data. LW, L-nW, and J-fZ carried out statistical analysis. LW and L-nW prepared the manuscript. LW, L-nW, J-fZ, W-hG, C-hJ, WT, W-lZ, JH, and J-lJ edited and reviewed the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors JH.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.627946/full#supplementary-material
Click here for additional data file. | FOR 5 CONSECUTIVE DAYS (5 MG/M2) | DrugDosageText | CC BY | 33708780 | 19,615,855 | 2021 |
What was the dosage of drug 'FLUDARABINE PHOSPHATE'? | Low-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study.
T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m2 daily for 5 days and repeated every 6-8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3-22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.
Introduction
Allogeneic stem cell transplantation (allo-HSCT) is a potentially curative therapy for malignant hematological diseases. Disease relapse remains a major cause of treatment failure (1, 2). The monitoring of disease-related parameters, such as measurable residual disease (MRD), can detect evidence of low-volume disease, which can serve as an indicator for emerging relapse (3). Hematopoietic chimerism analysis, which can distinguish residual recipient hematopoiesis from donor cells, is useful for the monitoring of allograft health and predicting imminent graft rejection, and can also be an indicator of potential relapse (2). The gold standard for quantitative chimerism analysis relies on the polymerase chain reaction (PCR)-based detection of variable number tandem repeats (VNTRs) or short tandem repeat (STR) polymorphisms in DNA from bone marrow or peripheral blood mononucleated cells or T cells, as recommended by the EuroChimerism Consortium (4–7).
Several studies have demonstrated that patients with mixed chimerism (MC) in either mononucleated cells or CD3+ T cells display a significantly higher incidence of relapse (40–90%) than those with complete donor chimerism (10–20%). The time between the detection of MC and relapse (median ~70 days) may permit timely therapeutic intervention (8–10). The rapid withdrawal of immunosuppression (RWIS) and preemptive donor lymphocyte infusion (DLI) may result in full donor chimerism (FDC) and are effective in reducing the relapse rate (RR) (11–14). However, RWIS and DLI have also been associated with complications, such as the development or aggravation of graft-versus-host disease (GvHD). Notably, MC without MRD does not necessarily equate to disease recurrence because the recrudescence of host hematopoiesis may represent normal hematopoiesis. In such a scenario, clinical decisions of immune modulation are complicated owing to the unnecessary risk of aggravation of GvHD (1, 2).
Epigenetic modulation of histone deacetylases (HDCs) such as sirturin-1 or methylation is important in maintaining normal function of hematopoietic stem cells and potentially regulating GvHD or graft versus leukemia effect (GvL) in the allo-HSCT settings (15–17). Hypomethylating agents (HMAs), administered either prophylactically or preemptively, are important treatment options after allo-HSCT for patients with acute myeloid leukemia (AML) or myelodysplasia (MDS) (18, 19). Multiple studies have demonstrated that HMAs exert significant immunomodulatory effects and are important for reducing post-transplantation relapse, and do so without inducing GvHD (20). In our previous study, we observed that low-dose decitabine (LD-DAC) converted MC into FDC in patients during maintenance therapy (21). In this pilot prospective study, we assessed the efficacy and safety of LD-DAC in the treatment of patients with MC in CD3+ T cells after allo-HSCT with myeloablative conditioning (MAC).
Methods
Study Design
This was an investigator-initiated, prospective, nonrandomized, single-arm, phase II clinical trial (NCT 03663751) to evaluate the efficacy and safety of LD-DAC as a monotherapy for patients with MC and who were also MRD-negative after allo-HSCT. The study was approved by the Human Ethics Committee of the Rui Jin Hospital and was conducted in accordance with the Declaration of Helsinki. The study was conducted in the Blood and Marrow Transplantation Center, Department of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. All enrolled patients provided written informed consent.
Study Protocol
The inclusion criteria were as follows: (1) adult patients (16–60) undergoing allo-HSCT with myeloablative conditioning from human leukocyte antigen (HLA)-matched sibling donors (MSDs), matched unrelated donors (MUDs), or haploidentical (Haplo) donors; (2) patients who achieved hematological engraftment and presented with a sustainable absolute neutrophil count (ANC) of >0.5 × 109/L not dependent on granulocyte colony-stimulating factor; (3) patients with hematological malignancies and presenting with measurable disease as indicated by immunophenotyping and/or molecular analysis; and (4) patients presented with MC (<99%) among T cells from either bone marrow or peripheral blood and who were MRD-negative in the bone marrow (<0.01%) after transplantation. The exclusion criteria were (1) patients with grade II-IV acute GvHD (aGvHD) or moderate to severe chronic GVHD (cGvHD) not responding to the treatment and (2) patients with severe complications such as life-threatening infections (bacterial, viral, or fungal), sinusoid obstructive syndrome (SOS), HSCT-associated thrombotic microangiopathy (TA-TMA), or posterior reversible encephalopathy syndrome (PRES) not responding to treatment.
All the enrolled patients received LD-DAC at 5 mg/m2 for 5 consecutive days. Chimerism monitoring was performed 4 weeks after the treatment. Patients who showed a favorable response were followed-up every 6–8 weeks. For patients who did not achieve a favorable response, the LD-DAC treatment was repeated every 6–8 weeks for up to 4 cycles. For patients undergoing immunosuppressive (IS) treatment, either as prophylaxis or for ongoing GvHD, RWIS was not implemented. For patients not receiving immunosuppressive treatment, no immunomodulatory therapy, such as interferon administration or DLI, were allowed. Patients were removed from the trial in the case of events such as the emergence of MRD, relapse, new onset, or aggravation of existing GvHD to grade III–IV aGvHD or moderate/severe cGvHD, life-threatening infection, SOS, TA-TMA, PRES, or other severe HSCT-associated complication (Figure 1).
Figure 1 Flow chart of the study design.
Definition of Response and Study Endpoints
Responses were assigned as follows: (1) Complete response (CR): patients achieving FDC (≥99%); (2) major response (MR): patients with increased donor chimerism (≥95%); (3) partial response (PR): patients with a 10% increase in the level of donor chimerism but that failed to reach 95%; and (4) no response (NR): patients with no or less than a 10% increase in the level of donor chimerism, and that failed to reach 95%. CRs and MRs were considered favorable, whereas PRs or NRs were considered unfavorable.
The primary endpoint of the study was achieving favorable responses (CR and MR) at 6 months after enrollment. Secondary endpoints included unfavorable events, namely, newly developed grade III–IV aGvHD or moderate to severe cGvHD, graft failure, relapse, or nonrelapse mortality (NRM) documented 6 months after enrollment; and survival data, including overall survival (OS), RR, NRM, and event-free survival (EFS) at 2 years after allo-HSCT.
Chimerism Analysis
Genomic DNA was extracted from 200 μL of CD3+ T cells (EDTA-treated) obtained from whole blood or bone marrow. A total of 25 ng of the extracted DNA was used for the amplification of 16 autosomal STRs (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, D5S818, D13S317, D16S539, D2S1338, D19S433, VWA, D12S391, D18S51, Amel, D6S1043, and FGA) using the AmpFLSTR® Huaxia™ PCR Direct Amplification Kit (Invitrogen, Beijing, China). A total of 0.5 μL of the amplified product was mixed with 9 μL of Hi-Di formamide and 0.5 μL of GeneScan-500 Liz molecular weight marker for electrophoresis run on an ABI 3130 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). GeneMapper1 v3.2.1 was adopted to analyze the genotype of each site based on the length of the DNA fragments and allelic ladders. The chimerism values were calculated from the observed peak areas of the informative markers. The calculation procedure was standardized to obtain reproducible chimerism values. The length of the labeled recipient and donor alleles was determined through the analysis of donor and recipient DNA isolated before transplantation. The allele lengths of all the markers were scored. The relative positions of the donor and recipient alleles of a given marker determined its applicability to the calculation of mosaicism, as described by Nollet et al. (22). Chimerism analysis had a sensitivity of 1% and ≥99% was considered to be FDC.
Sample Size Estimation and Statistical Analysis
This was a phase II study based on Simon's two-stage design (23). The study hypothesis was based on an expected favorable response rate ≥80% with an unacceptable favorable response rate ≤50%. The trial would be stopped early if the number of patients showing a favorable response failed to meet the relevant criteria (Supplementary Table 1).
Concerning safety, severe unfavorable events were defined as detectable MRD or disease relapse, graft failure, NRM of any cause, newly developed or aggravated aGvHD to grade III–IV or moderate to severe cGvHD, life-threatening infections, or other allo-HSCT-associated complications such as SOS, TA-TMA, and PRES. A 30% value was set as the unacceptable level of overall incidence of severe adverse events following, which the study would be stopped early based on the continuous monitoring for toxicity using Pocock-type boundary (Supplementary Table 2) (24). Survival rates were calculated using Kaplan–Meier estimates (25). OS was calculated from day 0 to the date of death from any cause. EFS was calculated from day 0 to the date of occurrence of aGVHD (III–IV) or moderate to severe cGVHD, graft failure, relapse, or death of all causes.
Results
Patient Characteristics
A total of 14 patients were enrolled in the study. All the patients had hematological malignancies and received MAC mostly with fludarabine (150 mg/m2) and busulfan (12.8 mg/kg) or sequential high-dose chemotherapy (cladribine + cytarabine + etoposide) followed by fludarabine (150 mg/m2) and busulfan (9.6 mg/kg) conditioning. For myeloid leukemia, GvHD prophylaxis was a standard regimen comprising cyclosporin plus methotrexate and mycophenolate mofetil, with anti-thymoglobulin (ATG) 6 or 10 mg/kg for HLA-MUD or mismatched related donor transplantation. For patients with lymphoid malignancies, GvHD prophylaxis was post-transplantation cyclophosphamide [50 mg/(kg·day−1) at days +3 and +4] with tacrolimus starting from day+5 or low-dose ATG [2.5 mg/(kg·day−1) at day +15 or after neutrophil engraftment in MUD and haplo settings]. All these patients achieved negative MRD day 28–30 after allo-HSCT and remained negative when enrolled in this study. The characteristics of the patients are shown in Table 1.
Table 1 Patient characteristics and outcomes.
UPN #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 #13 #14
Age 45 20 45 51 20 51 16 40 29 20 60 20 20 16
Sex M M F F M F M M M M M F M M
Diagnosis CML ALL AML MDS-EB2 ALL AML ALL AML Sezary T-NHL AML AML Ph+ ALL ALL
Disease status at transplant CP3- T315I CR1 CR1 NR CR1 CR1 CR1 CR2 NR CR3 MRD+ CR1 MRD+ CR1 CR1 CR1
Donor type Haplo MUD Sib MUD Sib Sib Haplo Sib MUD Haplo Sib MUD Haplo Sib
GvHD status Skin cGvHD / / / / / / / / / / / / /
IS prophylaxis FK506 FK506 / CsA FK506 / / / / FK506 FK506 FK506 FK506 FK506
Time of MC +90 +60 +100 +60 +76 +120 +101 +157 +180 +92 +35 +75 +30 +30
MRD level – – – – – – – – – – – – – –
DC level 89% 97% 82% 76% 89% 93% 91% 89% 93% 92% 81% 91% 59% 85%
DC after the first LD-DAC >99% 95% 89% 94% 81% >99% 95% >99% 96% 95% 93% 97% 2% 98%
DC after the second LD-DAC / >99% >99% 86% 90% / 95% / >99% >99% >99% 99% / /
DC after the third LD-DAC / / / 86% 96% / 2% / / / / / / /
DC level at six-month >99% >99% >99% 86% 96% >99% 2% >99% >99% >99% >99% 99% 0 98%
Six-month response CR CR CR PR MR CR NR CR CR CR CR CR NR MR
GvHD* – – – + – – – – – – + – – –
Relapse** – – – + – – – – – – – – – –
Graft failure*** – – – – – – + – – – – – + –
NRM – – – – – – – – – – + – – –
Inremission + + + + + + + + + + – + + +
OS (days) 878+ 822+ 803+ 709+ 546+ 529+ 509+ 456+ 418+ 287+ 372 321+ 257+ 130+
UPN, unique patient number; CML, chronic myelocytic leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; MDS EB2, myelodysplastic syndrome with excess blasts 2; T-NHL, T cell non-Hodgkin's lymphoma; Ph+, Philadelphia chromosome-positive; CP3, third chronic phase; CR1/2/3, first/second/third complete remission; NR, nonremission; MRD+, measurable residual disease-positive; Haplo, haploidentical; MUD, matched unrelated donor; Sib, sibling; cGvHD, chronic graft versus host disease; IS, immunosuppressor; CsA, cyclosporine A; MC, mixed chimerism; DC, donor chimerism; LD-DAC, low-dose decitabine; CR, complete response; PR, partial response; MR, major response; NR, no response; NRM, nonrelapse mortality; OS, overall survival.
* UPN#4 presented newly developed grade II acute GvHD (skin rash) which progressed to chronic skin GvHD; UPN#11 developed bronchiolitis obliterans (BO) 4 months after the second cycle of LD-DAC and eventually died of a lung infection.
** Relapse: UPN#4 progressed to AML on day +335 and received azacytidine plus venetoclax followed by a second allogeneic hematopoietic stem cell transplantation (allo-HSCT).
*** UPN#7 and UPN#13 both developed graft failure after ganciclovir treatment of CMV DNAemia. UPN#7 subsequently received a second allo-HSCT from a MUD and was in remission 9 months later; UPN#13 underwent a second allo-HSCT from a MUD and was in remission 2months after the second allo-HSCT.
MC was documented from day +30 to day +180 after allo-HSCT, and the donor chimerism level ranged from 59 to 97%. A total of 26 cycles of LD-DAC were given. Five patients received one cycle of LD-DAC, six patients received two, and three received three.
Response to LD-DAC Treatment
A total of 11 patients showed a favorable response (78.6%). Nine of them achieved CR (FDC ≥ 99%)—three after one cycle of LD-DAC, and six after two cycles. Two patients achieved MR (>95% of donor chimerism) after one and three cycles of LD-DAC, respectively. Notably, at 6 months after enrollment or the last follow-up, all of these patients maintained their responses for a median of 372 days (132–780; Figure 2).
Figure 2 Timing and outcome of chimerism analysis among the enrolled patients. Shown is the chimerism outcome for each patient enrolled in the study at different time points. The level of donor chimerism is indicated by the color of the closed circle. The inverted triangle indicates the time of low-dose decitabine (LD-DAC) treatment given for each patient.
Three patients failed to reach a sustainable favorable response. Patient #4 achieved only a PR after two cycles of LD-DAC, with a donor chimerism level of 94%. Patient #7 had a quick MR after the first cycle of LD-DAC but rapidly experienced graft failure after ganciclovir treatment for cytomegalovirus (CMV) reactivation. Patient #13, with 59% donor chimerism, failed to respond and had graft failure 3 weeks after one cycle of LD-DAC (Figure 2).
Overall, 6 months after enrollment, 10 patients maintained a favorable response without major unfavorable events. Four patients had unfavorable events, including relapse with initial PR (patient #4), loss of initial response with graft failure (patient #7), NR with graft failure (patient #13), and development of moderate to severe cGvHD and NRM (patient #11).
Toxicity and Complications
Each adverse event was graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. For the 26 cycles of LD-DAC given, including the two that resulted in graft failure, grade III–IV hematological toxicities were observed, including neutropenia and thrombocytopenia (Table 2). If the two cycles that resulted in graft failure are excluded, the grade IV incidence of neutropenia and thrombocytopenia was 33.3% for both parameters. All the patients recovered rapidly, mostly within 7 days, and no life-threatening neutropenic fever and/or bleeding episodes were observed. No severe nonhematological toxicities were documented.
Table 2 Hematological toxicities after LD-DAC treatment (26 cycles).
WBC (%) ANC (%) Hb (%) PLT (%)
None 0 2 (7.7) 1 (3.8) 1 (3.8)
Grade 1 3 (11.5) 3 (11.5) 8 (30.8) 4 (15.4)
Grade 2 7 (26.9) 5 (19.2) 7 (26.9) 4 (15.4)
Grade 3 6 (23.1) 7 (26.9) 9 (34.6) 8 (30.8)
Grade 4 10 (38.5*) 9 (34.6*) 1 (3.8*) 9 (34.6*)
LD-DAC, low-dose decitabine; WBC, white blood cell count; ANC, absolute neutrophil count; Hb, hemoglobin; PLT, platelet count.
* If the two cycles of treatment that were associated with graft failure are excluded, the grade IV toxicities were 9 (37.5%), 8 (33.3%), 0, and 8 (33.3%) for WBC, ANC, Hb, and PLT, respectively.
There was no aggravation of existing GvHD (patient #1). Patient #4 experienced a new-onset skin rash 4 days after the first LD-DAC treatment, which developed into cGVHD that did not respond well to tacrolimus and was eventually controlled with sirolimus. Patient #11 developed symptoms of dyspnea 4 months after the second LD-DAC treatment and was later diagnosed with bronchiolitis obliterans (BO). Otherwise, there were no life-threatening infections, SOS, TA-TMA, PRES, or other severe complications associated with the HSCT.
Follow-Up Outcome
At the last follow-up on September 30, 2020, the median time of follow-up was 526 days after allo-HSCT (130–878) and 372 days (132–780) after enrollment. A total of 13 patients were alive, including 10 without disease relapse or progression.
Three patients were removed from the study owing to relapse and/or secondary graft failure. Patient #4, who had MDS, progressed to AML 11 months after the first MUD allo-HSCT. The patient was rescued by azacytidine plus venetoclax treatment followed by a second Haplo donor allo-HSCT and was alive and in remission 12 months after the second allo-HSCT. The two patients (#7 and #13) who developed graft failure were rescued following a second allo-HSCT from a MUD and were also alive and in remission nine and 2 months later, respectively. Only patient #11, who developed BO after treatment, died of pulmonary infection (Table 1). Overall, the estimated 2-year OS and EFS after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively (Figure 3).
Figure 3 Kaplan–Meier curve for overall survival (OS) and event-free survival (EFS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) among the enrolled patients. OS, solid line; EFS, dotted line.
Discussion
Various studies have demonstrated that early MC in patients undergoing allo-HSCT with MAC may be suggestive of a relapse. The relapse rate can be as high as 70–90% for patients with reduced donor chimerism, whereas it is only 10–35% for patients with FDC (8–11). In patients with AML/MDS, testing for mixed T lymphocyte chimerism at day +90 to 120 after allo-HSCT is reported to be a promising approach for detecting patients with pending relapse, while preemptive DLI to maintain full donor T cell chimerism may prevent relapse (12). In the setting of acute lymphoblastic leukemia (ALL) after allo-HSCT, based on the comparison of lineage-sorted donor cell chimerism and quantitative PCR analysis of disease-specific genetic rearrangements to detect MRD, Wethmar et al. demonstrated that two measurements were similarly and complementarily effective as indicators of hematological relapse (50 vs. 4%, respectively; p < 0.0001) and decreased OS (47 vs. 87%, respectively; p = 0.004) (26). Terwey et al. also showed that, besides its role in MRD monitoring, MC analysis could additionally provide information for impending relapse. Integrating MRD and chimerism analysis allowed for optimal clinical judgment and decision-making to reduce relapse rates through preemptive interventions (27).
In this study, we focused on a subgroup of patients exhibiting MC of CD3+ T cells either in bone marrow or in peripheral blood, and who were MRD-negative, based on flow cytometry and/or molecular analysis early after allo-HSCT with MAC. In patients presenting with MC, several clinical outcomes can be expected. For instance, some may spontaneously recover to FDC without intervention or remain with stable MC without relapse. An increased loss of donor chimerism with the development of neutropenia or pancytopenia, leading to graft failure, may also occur, while most patients with persistent or increased levels of MC may eventually become MRD-positive and experience disease relapse. To prevent MC-associated relapse and/or graft failure, immune modulation such as RWIS and/or DLI are routinely considered. Based on multivariate analysis, a recent report demonstrated that two consecutive increases in MC in the peripheral blood of patients was a strong indicator for relapse (p < 0.0001) and immunomodulatory strategies such as RWIS or DLI could significantly decrease this relapse rate (15.7 vs. 57.6%, p = 0.0007) (28). Notably, immune modulation is limited in patients with previous grade III–IV aGvHD or with moderate to severe cGvHD. The rate of new-onset GvHD can be as high as ~40%, including grade II–IV aGVHD- or moderate to severe cGVHD. With DLI, GvHD-associated mortality ranges from 4 to 7% (29, 30).
In recent years, HMAs have been shown to exert significant immunomodulatory effects, and clinical studies have been undertaken to assess the usefulness of HMAs for the treatment or prevention of relapse in patients with AML or MDS after allo-HSCT (14, 18–20). In this pilot study, we focused on such a group of patients, who were considered to have the potential for an increased risk of relapse or graft loss, but not necessarily imminent relapse. To rule out the possible effects of other immunomodulatory therapies, RWIS and/or DLI were not implemented in the enrolled patients.
Of the 14 enrolled patients, 11 achieved a FR (9 achieved a CR and 2 a MR) after one to three cycles of LD-DAC treatment. Despite a speedy MR after initial treatment, one patient rapidly experienced secondary graft failure following preemptive therapy for CMV reactivation, while another patient displayed a PR, with skin rash as a cGvHD. Only one patient, who presented with a very low level of donor chimerism (<60%), failed to respond to LD-DAC treatment and rapidly developed secondary graft failure. In terms of safety, the treatment was well tolerated with exerted limited hematological and nonhematological toxicities. More importantly, only two patients developed new symptoms of cGVHD several days or months after the treatment. Most of the patients who achieved and maintained FDC remained alive and in remission without significant clinical complications. Adverse events, including treatment failure, severe GvHD, relapse, and NRM, were documented in only four patients and were acceptable based on continuous monitoring for toxicity using Pocock-type boundary. These data suggested that LD-DAC monotherapy has potential as a treatment option for patients with MC and who are MRD-negative.
There were still questions unanswered regarding to the LD-DAC treatment particularly the influence of diseases (myeloid vs. lymphoid malignancies), donor type (MSD vs. MUD or haplo), GVHD prophylaxis protocol (PTCY vs. CNI-based regimen or ATG vs. no ATG), GVHD status (previous GVHD vs. No GVHD), and the immunosuppressive treatment at LD-DAC treatment (No IS vs. ongoing IS).
The small number of patients enrolled limited the ability to draw definitive conclusions. However, ~80% of the patients responded favorably to LD-DAC treatment with acceptable toxicity, suggesting that LD-DAC may be a potential alternative to RWIS and DLI. Additional prospective studies with larger sample sizes are warranted to confirm the clinical benefits of LD-DAC.
Data Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
The studies involving human participants were reviewed and approved by Ruijin Hospital Ethics Committee, Shanghai Jiao Tong University School of Medicine. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.
Author Contributions
LW, L-nW, JH, and J-lJ conceived and designed the study and acquired, analyzed, and interpreted the data. LW, L-nW, and J-fZ carried out statistical analysis. LW and L-nW prepared the manuscript. LW, L-nW, J-fZ, W-hG, C-hJ, WT, W-lZ, JH, and J-lJ edited and reviewed the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors JH.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.627946/full#supplementary-material
Click here for additional data file. | 150 MG/M2 | DrugDosageText | CC BY | 33708780 | 19,615,855 | 2021 |
What was the dosage of drug 'TACROLIMUS'? | Low-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study.
T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m2 daily for 5 days and repeated every 6-8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3-22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.
Introduction
Allogeneic stem cell transplantation (allo-HSCT) is a potentially curative therapy for malignant hematological diseases. Disease relapse remains a major cause of treatment failure (1, 2). The monitoring of disease-related parameters, such as measurable residual disease (MRD), can detect evidence of low-volume disease, which can serve as an indicator for emerging relapse (3). Hematopoietic chimerism analysis, which can distinguish residual recipient hematopoiesis from donor cells, is useful for the monitoring of allograft health and predicting imminent graft rejection, and can also be an indicator of potential relapse (2). The gold standard for quantitative chimerism analysis relies on the polymerase chain reaction (PCR)-based detection of variable number tandem repeats (VNTRs) or short tandem repeat (STR) polymorphisms in DNA from bone marrow or peripheral blood mononucleated cells or T cells, as recommended by the EuroChimerism Consortium (4–7).
Several studies have demonstrated that patients with mixed chimerism (MC) in either mononucleated cells or CD3+ T cells display a significantly higher incidence of relapse (40–90%) than those with complete donor chimerism (10–20%). The time between the detection of MC and relapse (median ~70 days) may permit timely therapeutic intervention (8–10). The rapid withdrawal of immunosuppression (RWIS) and preemptive donor lymphocyte infusion (DLI) may result in full donor chimerism (FDC) and are effective in reducing the relapse rate (RR) (11–14). However, RWIS and DLI have also been associated with complications, such as the development or aggravation of graft-versus-host disease (GvHD). Notably, MC without MRD does not necessarily equate to disease recurrence because the recrudescence of host hematopoiesis may represent normal hematopoiesis. In such a scenario, clinical decisions of immune modulation are complicated owing to the unnecessary risk of aggravation of GvHD (1, 2).
Epigenetic modulation of histone deacetylases (HDCs) such as sirturin-1 or methylation is important in maintaining normal function of hematopoietic stem cells and potentially regulating GvHD or graft versus leukemia effect (GvL) in the allo-HSCT settings (15–17). Hypomethylating agents (HMAs), administered either prophylactically or preemptively, are important treatment options after allo-HSCT for patients with acute myeloid leukemia (AML) or myelodysplasia (MDS) (18, 19). Multiple studies have demonstrated that HMAs exert significant immunomodulatory effects and are important for reducing post-transplantation relapse, and do so without inducing GvHD (20). In our previous study, we observed that low-dose decitabine (LD-DAC) converted MC into FDC in patients during maintenance therapy (21). In this pilot prospective study, we assessed the efficacy and safety of LD-DAC in the treatment of patients with MC in CD3+ T cells after allo-HSCT with myeloablative conditioning (MAC).
Methods
Study Design
This was an investigator-initiated, prospective, nonrandomized, single-arm, phase II clinical trial (NCT 03663751) to evaluate the efficacy and safety of LD-DAC as a monotherapy for patients with MC and who were also MRD-negative after allo-HSCT. The study was approved by the Human Ethics Committee of the Rui Jin Hospital and was conducted in accordance with the Declaration of Helsinki. The study was conducted in the Blood and Marrow Transplantation Center, Department of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. All enrolled patients provided written informed consent.
Study Protocol
The inclusion criteria were as follows: (1) adult patients (16–60) undergoing allo-HSCT with myeloablative conditioning from human leukocyte antigen (HLA)-matched sibling donors (MSDs), matched unrelated donors (MUDs), or haploidentical (Haplo) donors; (2) patients who achieved hematological engraftment and presented with a sustainable absolute neutrophil count (ANC) of >0.5 × 109/L not dependent on granulocyte colony-stimulating factor; (3) patients with hematological malignancies and presenting with measurable disease as indicated by immunophenotyping and/or molecular analysis; and (4) patients presented with MC (<99%) among T cells from either bone marrow or peripheral blood and who were MRD-negative in the bone marrow (<0.01%) after transplantation. The exclusion criteria were (1) patients with grade II-IV acute GvHD (aGvHD) or moderate to severe chronic GVHD (cGvHD) not responding to the treatment and (2) patients with severe complications such as life-threatening infections (bacterial, viral, or fungal), sinusoid obstructive syndrome (SOS), HSCT-associated thrombotic microangiopathy (TA-TMA), or posterior reversible encephalopathy syndrome (PRES) not responding to treatment.
All the enrolled patients received LD-DAC at 5 mg/m2 for 5 consecutive days. Chimerism monitoring was performed 4 weeks after the treatment. Patients who showed a favorable response were followed-up every 6–8 weeks. For patients who did not achieve a favorable response, the LD-DAC treatment was repeated every 6–8 weeks for up to 4 cycles. For patients undergoing immunosuppressive (IS) treatment, either as prophylaxis or for ongoing GvHD, RWIS was not implemented. For patients not receiving immunosuppressive treatment, no immunomodulatory therapy, such as interferon administration or DLI, were allowed. Patients were removed from the trial in the case of events such as the emergence of MRD, relapse, new onset, or aggravation of existing GvHD to grade III–IV aGvHD or moderate/severe cGvHD, life-threatening infection, SOS, TA-TMA, PRES, or other severe HSCT-associated complication (Figure 1).
Figure 1 Flow chart of the study design.
Definition of Response and Study Endpoints
Responses were assigned as follows: (1) Complete response (CR): patients achieving FDC (≥99%); (2) major response (MR): patients with increased donor chimerism (≥95%); (3) partial response (PR): patients with a 10% increase in the level of donor chimerism but that failed to reach 95%; and (4) no response (NR): patients with no or less than a 10% increase in the level of donor chimerism, and that failed to reach 95%. CRs and MRs were considered favorable, whereas PRs or NRs were considered unfavorable.
The primary endpoint of the study was achieving favorable responses (CR and MR) at 6 months after enrollment. Secondary endpoints included unfavorable events, namely, newly developed grade III–IV aGvHD or moderate to severe cGvHD, graft failure, relapse, or nonrelapse mortality (NRM) documented 6 months after enrollment; and survival data, including overall survival (OS), RR, NRM, and event-free survival (EFS) at 2 years after allo-HSCT.
Chimerism Analysis
Genomic DNA was extracted from 200 μL of CD3+ T cells (EDTA-treated) obtained from whole blood or bone marrow. A total of 25 ng of the extracted DNA was used for the amplification of 16 autosomal STRs (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, D5S818, D13S317, D16S539, D2S1338, D19S433, VWA, D12S391, D18S51, Amel, D6S1043, and FGA) using the AmpFLSTR® Huaxia™ PCR Direct Amplification Kit (Invitrogen, Beijing, China). A total of 0.5 μL of the amplified product was mixed with 9 μL of Hi-Di formamide and 0.5 μL of GeneScan-500 Liz molecular weight marker for electrophoresis run on an ABI 3130 Genetic Analyzer (Applied Biosystems, Foster City, CA, USA). GeneMapper1 v3.2.1 was adopted to analyze the genotype of each site based on the length of the DNA fragments and allelic ladders. The chimerism values were calculated from the observed peak areas of the informative markers. The calculation procedure was standardized to obtain reproducible chimerism values. The length of the labeled recipient and donor alleles was determined through the analysis of donor and recipient DNA isolated before transplantation. The allele lengths of all the markers were scored. The relative positions of the donor and recipient alleles of a given marker determined its applicability to the calculation of mosaicism, as described by Nollet et al. (22). Chimerism analysis had a sensitivity of 1% and ≥99% was considered to be FDC.
Sample Size Estimation and Statistical Analysis
This was a phase II study based on Simon's two-stage design (23). The study hypothesis was based on an expected favorable response rate ≥80% with an unacceptable favorable response rate ≤50%. The trial would be stopped early if the number of patients showing a favorable response failed to meet the relevant criteria (Supplementary Table 1).
Concerning safety, severe unfavorable events were defined as detectable MRD or disease relapse, graft failure, NRM of any cause, newly developed or aggravated aGvHD to grade III–IV or moderate to severe cGvHD, life-threatening infections, or other allo-HSCT-associated complications such as SOS, TA-TMA, and PRES. A 30% value was set as the unacceptable level of overall incidence of severe adverse events following, which the study would be stopped early based on the continuous monitoring for toxicity using Pocock-type boundary (Supplementary Table 2) (24). Survival rates were calculated using Kaplan–Meier estimates (25). OS was calculated from day 0 to the date of death from any cause. EFS was calculated from day 0 to the date of occurrence of aGVHD (III–IV) or moderate to severe cGVHD, graft failure, relapse, or death of all causes.
Results
Patient Characteristics
A total of 14 patients were enrolled in the study. All the patients had hematological malignancies and received MAC mostly with fludarabine (150 mg/m2) and busulfan (12.8 mg/kg) or sequential high-dose chemotherapy (cladribine + cytarabine + etoposide) followed by fludarabine (150 mg/m2) and busulfan (9.6 mg/kg) conditioning. For myeloid leukemia, GvHD prophylaxis was a standard regimen comprising cyclosporin plus methotrexate and mycophenolate mofetil, with anti-thymoglobulin (ATG) 6 or 10 mg/kg for HLA-MUD or mismatched related donor transplantation. For patients with lymphoid malignancies, GvHD prophylaxis was post-transplantation cyclophosphamide [50 mg/(kg·day−1) at days +3 and +4] with tacrolimus starting from day+5 or low-dose ATG [2.5 mg/(kg·day−1) at day +15 or after neutrophil engraftment in MUD and haplo settings]. All these patients achieved negative MRD day 28–30 after allo-HSCT and remained negative when enrolled in this study. The characteristics of the patients are shown in Table 1.
Table 1 Patient characteristics and outcomes.
UPN #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 #13 #14
Age 45 20 45 51 20 51 16 40 29 20 60 20 20 16
Sex M M F F M F M M M M M F M M
Diagnosis CML ALL AML MDS-EB2 ALL AML ALL AML Sezary T-NHL AML AML Ph+ ALL ALL
Disease status at transplant CP3- T315I CR1 CR1 NR CR1 CR1 CR1 CR2 NR CR3 MRD+ CR1 MRD+ CR1 CR1 CR1
Donor type Haplo MUD Sib MUD Sib Sib Haplo Sib MUD Haplo Sib MUD Haplo Sib
GvHD status Skin cGvHD / / / / / / / / / / / / /
IS prophylaxis FK506 FK506 / CsA FK506 / / / / FK506 FK506 FK506 FK506 FK506
Time of MC +90 +60 +100 +60 +76 +120 +101 +157 +180 +92 +35 +75 +30 +30
MRD level – – – – – – – – – – – – – –
DC level 89% 97% 82% 76% 89% 93% 91% 89% 93% 92% 81% 91% 59% 85%
DC after the first LD-DAC >99% 95% 89% 94% 81% >99% 95% >99% 96% 95% 93% 97% 2% 98%
DC after the second LD-DAC / >99% >99% 86% 90% / 95% / >99% >99% >99% 99% / /
DC after the third LD-DAC / / / 86% 96% / 2% / / / / / / /
DC level at six-month >99% >99% >99% 86% 96% >99% 2% >99% >99% >99% >99% 99% 0 98%
Six-month response CR CR CR PR MR CR NR CR CR CR CR CR NR MR
GvHD* – – – + – – – – – – + – – –
Relapse** – – – + – – – – – – – – – –
Graft failure*** – – – – – – + – – – – – + –
NRM – – – – – – – – – – + – – –
Inremission + + + + + + + + + + – + + +
OS (days) 878+ 822+ 803+ 709+ 546+ 529+ 509+ 456+ 418+ 287+ 372 321+ 257+ 130+
UPN, unique patient number; CML, chronic myelocytic leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; MDS EB2, myelodysplastic syndrome with excess blasts 2; T-NHL, T cell non-Hodgkin's lymphoma; Ph+, Philadelphia chromosome-positive; CP3, third chronic phase; CR1/2/3, first/second/third complete remission; NR, nonremission; MRD+, measurable residual disease-positive; Haplo, haploidentical; MUD, matched unrelated donor; Sib, sibling; cGvHD, chronic graft versus host disease; IS, immunosuppressor; CsA, cyclosporine A; MC, mixed chimerism; DC, donor chimerism; LD-DAC, low-dose decitabine; CR, complete response; PR, partial response; MR, major response; NR, no response; NRM, nonrelapse mortality; OS, overall survival.
* UPN#4 presented newly developed grade II acute GvHD (skin rash) which progressed to chronic skin GvHD; UPN#11 developed bronchiolitis obliterans (BO) 4 months after the second cycle of LD-DAC and eventually died of a lung infection.
** Relapse: UPN#4 progressed to AML on day +335 and received azacytidine plus venetoclax followed by a second allogeneic hematopoietic stem cell transplantation (allo-HSCT).
*** UPN#7 and UPN#13 both developed graft failure after ganciclovir treatment of CMV DNAemia. UPN#7 subsequently received a second allo-HSCT from a MUD and was in remission 9 months later; UPN#13 underwent a second allo-HSCT from a MUD and was in remission 2months after the second allo-HSCT.
MC was documented from day +30 to day +180 after allo-HSCT, and the donor chimerism level ranged from 59 to 97%. A total of 26 cycles of LD-DAC were given. Five patients received one cycle of LD-DAC, six patients received two, and three received three.
Response to LD-DAC Treatment
A total of 11 patients showed a favorable response (78.6%). Nine of them achieved CR (FDC ≥ 99%)—three after one cycle of LD-DAC, and six after two cycles. Two patients achieved MR (>95% of donor chimerism) after one and three cycles of LD-DAC, respectively. Notably, at 6 months after enrollment or the last follow-up, all of these patients maintained their responses for a median of 372 days (132–780; Figure 2).
Figure 2 Timing and outcome of chimerism analysis among the enrolled patients. Shown is the chimerism outcome for each patient enrolled in the study at different time points. The level of donor chimerism is indicated by the color of the closed circle. The inverted triangle indicates the time of low-dose decitabine (LD-DAC) treatment given for each patient.
Three patients failed to reach a sustainable favorable response. Patient #4 achieved only a PR after two cycles of LD-DAC, with a donor chimerism level of 94%. Patient #7 had a quick MR after the first cycle of LD-DAC but rapidly experienced graft failure after ganciclovir treatment for cytomegalovirus (CMV) reactivation. Patient #13, with 59% donor chimerism, failed to respond and had graft failure 3 weeks after one cycle of LD-DAC (Figure 2).
Overall, 6 months after enrollment, 10 patients maintained a favorable response without major unfavorable events. Four patients had unfavorable events, including relapse with initial PR (patient #4), loss of initial response with graft failure (patient #7), NR with graft failure (patient #13), and development of moderate to severe cGvHD and NRM (patient #11).
Toxicity and Complications
Each adverse event was graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. For the 26 cycles of LD-DAC given, including the two that resulted in graft failure, grade III–IV hematological toxicities were observed, including neutropenia and thrombocytopenia (Table 2). If the two cycles that resulted in graft failure are excluded, the grade IV incidence of neutropenia and thrombocytopenia was 33.3% for both parameters. All the patients recovered rapidly, mostly within 7 days, and no life-threatening neutropenic fever and/or bleeding episodes were observed. No severe nonhematological toxicities were documented.
Table 2 Hematological toxicities after LD-DAC treatment (26 cycles).
WBC (%) ANC (%) Hb (%) PLT (%)
None 0 2 (7.7) 1 (3.8) 1 (3.8)
Grade 1 3 (11.5) 3 (11.5) 8 (30.8) 4 (15.4)
Grade 2 7 (26.9) 5 (19.2) 7 (26.9) 4 (15.4)
Grade 3 6 (23.1) 7 (26.9) 9 (34.6) 8 (30.8)
Grade 4 10 (38.5*) 9 (34.6*) 1 (3.8*) 9 (34.6*)
LD-DAC, low-dose decitabine; WBC, white blood cell count; ANC, absolute neutrophil count; Hb, hemoglobin; PLT, platelet count.
* If the two cycles of treatment that were associated with graft failure are excluded, the grade IV toxicities were 9 (37.5%), 8 (33.3%), 0, and 8 (33.3%) for WBC, ANC, Hb, and PLT, respectively.
There was no aggravation of existing GvHD (patient #1). Patient #4 experienced a new-onset skin rash 4 days after the first LD-DAC treatment, which developed into cGVHD that did not respond well to tacrolimus and was eventually controlled with sirolimus. Patient #11 developed symptoms of dyspnea 4 months after the second LD-DAC treatment and was later diagnosed with bronchiolitis obliterans (BO). Otherwise, there were no life-threatening infections, SOS, TA-TMA, PRES, or other severe complications associated with the HSCT.
Follow-Up Outcome
At the last follow-up on September 30, 2020, the median time of follow-up was 526 days after allo-HSCT (130–878) and 372 days (132–780) after enrollment. A total of 13 patients were alive, including 10 without disease relapse or progression.
Three patients were removed from the study owing to relapse and/or secondary graft failure. Patient #4, who had MDS, progressed to AML 11 months after the first MUD allo-HSCT. The patient was rescued by azacytidine plus venetoclax treatment followed by a second Haplo donor allo-HSCT and was alive and in remission 12 months after the second allo-HSCT. The two patients (#7 and #13) who developed graft failure were rescued following a second allo-HSCT from a MUD and were also alive and in remission nine and 2 months later, respectively. Only patient #11, who developed BO after treatment, died of pulmonary infection (Table 1). Overall, the estimated 2-year OS and EFS after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively (Figure 3).
Figure 3 Kaplan–Meier curve for overall survival (OS) and event-free survival (EFS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) among the enrolled patients. OS, solid line; EFS, dotted line.
Discussion
Various studies have demonstrated that early MC in patients undergoing allo-HSCT with MAC may be suggestive of a relapse. The relapse rate can be as high as 70–90% for patients with reduced donor chimerism, whereas it is only 10–35% for patients with FDC (8–11). In patients with AML/MDS, testing for mixed T lymphocyte chimerism at day +90 to 120 after allo-HSCT is reported to be a promising approach for detecting patients with pending relapse, while preemptive DLI to maintain full donor T cell chimerism may prevent relapse (12). In the setting of acute lymphoblastic leukemia (ALL) after allo-HSCT, based on the comparison of lineage-sorted donor cell chimerism and quantitative PCR analysis of disease-specific genetic rearrangements to detect MRD, Wethmar et al. demonstrated that two measurements were similarly and complementarily effective as indicators of hematological relapse (50 vs. 4%, respectively; p < 0.0001) and decreased OS (47 vs. 87%, respectively; p = 0.004) (26). Terwey et al. also showed that, besides its role in MRD monitoring, MC analysis could additionally provide information for impending relapse. Integrating MRD and chimerism analysis allowed for optimal clinical judgment and decision-making to reduce relapse rates through preemptive interventions (27).
In this study, we focused on a subgroup of patients exhibiting MC of CD3+ T cells either in bone marrow or in peripheral blood, and who were MRD-negative, based on flow cytometry and/or molecular analysis early after allo-HSCT with MAC. In patients presenting with MC, several clinical outcomes can be expected. For instance, some may spontaneously recover to FDC without intervention or remain with stable MC without relapse. An increased loss of donor chimerism with the development of neutropenia or pancytopenia, leading to graft failure, may also occur, while most patients with persistent or increased levels of MC may eventually become MRD-positive and experience disease relapse. To prevent MC-associated relapse and/or graft failure, immune modulation such as RWIS and/or DLI are routinely considered. Based on multivariate analysis, a recent report demonstrated that two consecutive increases in MC in the peripheral blood of patients was a strong indicator for relapse (p < 0.0001) and immunomodulatory strategies such as RWIS or DLI could significantly decrease this relapse rate (15.7 vs. 57.6%, p = 0.0007) (28). Notably, immune modulation is limited in patients with previous grade III–IV aGvHD or with moderate to severe cGvHD. The rate of new-onset GvHD can be as high as ~40%, including grade II–IV aGVHD- or moderate to severe cGVHD. With DLI, GvHD-associated mortality ranges from 4 to 7% (29, 30).
In recent years, HMAs have been shown to exert significant immunomodulatory effects, and clinical studies have been undertaken to assess the usefulness of HMAs for the treatment or prevention of relapse in patients with AML or MDS after allo-HSCT (14, 18–20). In this pilot study, we focused on such a group of patients, who were considered to have the potential for an increased risk of relapse or graft loss, but not necessarily imminent relapse. To rule out the possible effects of other immunomodulatory therapies, RWIS and/or DLI were not implemented in the enrolled patients.
Of the 14 enrolled patients, 11 achieved a FR (9 achieved a CR and 2 a MR) after one to three cycles of LD-DAC treatment. Despite a speedy MR after initial treatment, one patient rapidly experienced secondary graft failure following preemptive therapy for CMV reactivation, while another patient displayed a PR, with skin rash as a cGvHD. Only one patient, who presented with a very low level of donor chimerism (<60%), failed to respond to LD-DAC treatment and rapidly developed secondary graft failure. In terms of safety, the treatment was well tolerated with exerted limited hematological and nonhematological toxicities. More importantly, only two patients developed new symptoms of cGVHD several days or months after the treatment. Most of the patients who achieved and maintained FDC remained alive and in remission without significant clinical complications. Adverse events, including treatment failure, severe GvHD, relapse, and NRM, were documented in only four patients and were acceptable based on continuous monitoring for toxicity using Pocock-type boundary. These data suggested that LD-DAC monotherapy has potential as a treatment option for patients with MC and who are MRD-negative.
There were still questions unanswered regarding to the LD-DAC treatment particularly the influence of diseases (myeloid vs. lymphoid malignancies), donor type (MSD vs. MUD or haplo), GVHD prophylaxis protocol (PTCY vs. CNI-based regimen or ATG vs. no ATG), GVHD status (previous GVHD vs. No GVHD), and the immunosuppressive treatment at LD-DAC treatment (No IS vs. ongoing IS).
The small number of patients enrolled limited the ability to draw definitive conclusions. However, ~80% of the patients responded favorably to LD-DAC treatment with acceptable toxicity, suggesting that LD-DAC may be a potential alternative to RWIS and DLI. Additional prospective studies with larger sample sizes are warranted to confirm the clinical benefits of LD-DAC.
Data Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
The studies involving human participants were reviewed and approved by Ruijin Hospital Ethics Committee, Shanghai Jiao Tong University School of Medicine. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.
Author Contributions
LW, L-nW, JH, and J-lJ conceived and designed the study and acquired, analyzed, and interpreted the data. LW, L-nW, and J-fZ carried out statistical analysis. LW and L-nW prepared the manuscript. LW, L-nW, J-fZ, W-hG, C-hJ, WT, W-lZ, JH, and J-lJ edited and reviewed the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors JH.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.627946/full#supplementary-material
Click here for additional data file. | STARTING IN DAY5 | DrugDosageText | CC BY | 33708780 | 19,615,855 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lymphopenia'. | A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection.
Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that often develops in immunocompromised kidney-allograft recipients [1]. Several risks factors have been described: age, cytomegalovirus (CMV)-positive viremia, neutropenia, a lymphocyte count of <750/mm3 for more than 1 month (although a CD4+ T-cell of <200/µL is not a good biomarker in non-HIV patient), low plasma total gamma globulins, an acute-rejection episode, and immunosuppression treatment [2].
Renal toxicity was previously well described with high dose of trimethoprim-sulfamethoxazole (TMP-SMX) used in PJP treatment, i.e. acute tubular necrosis. SMX acts as a nephrotoxic agent through tubular precipitation and local production of crystal. Renal impermeant was also reported whatever the dose used, i.e. acute interstitial nephritis with immunologically induced hypersensitivity [3, 4]. Therefore, several studies have assessed the use of atovaquone or pentamidine to prevent PJP [5, 6]. Although the results are promising, TMP-SMX is still the first-choice prophylaxis [7]. In fact, the use of TMP-SMX as a prophylactic drug for PJP for 6–12 months after kidney transplantation can significantly decrease its incidence [8].
Herein, this case report describes the management and prevention of PJP in a kidney-allograft recipient receiving maintenance immunosuppressive therapy of belatacept, everolimus, plus corticosteroids.
Case Report
A 49-year-old HLA-sensitized male had end-stage renal disease that was secondary to autosomal dominant polycystic kidney disease, which had first been diagnosed when he was aged 30 years. In 2012, he received peritoneal dialysis for 1 year, and then hemodialysis for 2 years. He then received a kidney transplant in 2015 from a deceased donor. The donor and recipient were both CMV seronegative. The initial induction therapy was based on antithymocyte globulins (Thymoglobulin®, 0.5 mg/kg/day for 5 days) plus a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Serum-creatinine level at 1 month post-transplantation was 194 µmol/L.
At 3 months post-transplantation, serum creatinine had increased to 325 µmol/L, and the histology showed acute cellular rejection, which was treated with 3 boluses of methylprednisolone (10 mg/kg each). Despite the disappearance of inflammatory infiltrates within the interstitium (as seen in a follow-up allograft biopsy), renal function remained altered (creatinine at 319 µmol/L). In January 2017, the patient was converted to a belatacept-based calcineurin-free regimen, which led to recovery of renal function in 18 months: serum-creatinine level became 212 µmol/L. In August 2018, MMF was switched to the antiproliferative drug everolimus because of the risk of developing squamous-cell carcinoma. In December 2018, the patient developed a dry cough with a purulent sputum, although the fever resolved after 7 days of receiving amoxicillin. However, a few days later, he developed progressive and severe dyspnea, which led to his hospitalization 2 weeks later. In a clinical examination, the patient had tachypnea (32 breaths/min), and oxygen saturation was only at 88% in room air. Chest computed tomography showed diffuse bilateral alveolo-interstitial opacities suggesting an opportunistic infection (Fig. 1). The initial blood investigations revealed the following: C-reactive protein, 58 mg/L; low lymphocyte count (0.4 g/L) with no CD4 +T cells detected for 2 years; and hypogammaglobulinemia, i.e. immunoglobulin G (IgG) was 3.2 g/L compared to 4.2 g/L 5 months previously. Legionella, Aspergillus, and Pneumococcusantigenemias, Chlamydia, and Mycoplasma serologies, and a CMV DNAemia were all negative. Samples from a bronchoscopy and a bronchoalveolar lavage were negative for bacterial and viral pathogens (cultures and PCR testing) but revealed a high load of P. jirovecii DNA.
Because of respiratory gravity (i.e., PO2 = 60 mm Hg), the patient was given continuous oxygen support, intravenous corticosteroids (a single dose of 1 mg/kg of methylprednisone, which was then decreased to 0.5 mg/kg), and TMP-SMX (800/160 mg adjusted according to renal function).
After receiving these therapies for 7 days, the patient was weaned off oxygen, and his biological inflammatory markers were improved; however, there was 20% degradation in renal function (shown in Fig. 2). Because of the improved respiratory status but also the renal impairment we converted TMP-SMX to atovaquone for 21 days. The patient could then return home after 9 days of hospitalization with stable renal allograft function (creatinine: 227 µmol/L). Follow-up investigations showed normalization of CRP level, and renal allograft function returned to baseline values (creatinine: 200 µmol/L), and improvements were seen on radiological images. PJP prophylaxis for the next 6 months was pentamidine given as an aerosol monthly in the hospital. Belatacept (5 mg/kg every 4 weeks) was never stopped.
Discussion/Conclusion
At 3 years after renal ABO- and HLA-compatible allograft, and 2 years after conversion from tacrolimus to belatacept, our patient had developed acute PJP. He had presented several risks factors: immunosuppressive treatment (belatacept and everolimus), history of acute cellular rejection at 3 months post-transplantation, biological evidence of overimmunosuppression, i.e. low lymphocyte count with no CD4 T cell and decrease in IgG at 3.2 g/L. Indeed, antithymocyte globulins result in long-term lymphopenia. Crepin et al. [9] have reported that ATG delays thymic-dependent T cell reconstitution, increases the frequency of late-stage differentiated T cells, and promotes peripheral Treg expansion. Moreover, ATG is associated with persistent low values of T-cell relative telomere length and telomerase activity. Taken together, these data suggest that ATG induces accelerated immune senescence.
Hughes et al. [10] compared treating acute PJP with atovaquone or TMP-SMX. Patients treated with atovaquone “more often had no response” and had a higher mortality rate (7 vs. 0.6%, p = 0.003). Thus, TMP-SMX was the first treatment recommended to treat acute PJP [7]. At admission, our patient presented with acute-phase PJP with gravity criteria (he needed oxygen: PO2 = 60 mm Hg): at that time, the benefit-risk balance favored an aggressive induction treatment. Nevertheless, after 1 week, the benefit-risk balance became reversed in favor of preserving renal function according to respiratory improvement status. Thus, our patient was switched to receive atovaquone instead. After the induction treatment, he received pentamidine as the prophylaxis.
Belatacept, a new costimulation blocker has attracted interest as a treatment to preserve renal function, and improved cardiovascular/metabolic risk profile without infectious alarm signal confirmed by Vicenti and al. [11] after 7 years of use. Specific studies about early [12] or late [13] conversion to belatacept did not report PJP. The first case of lethal PCP under belatacept was described by Haidinger et al. [14] 4 years after transplantation in a multi-infected patient. Then, three other cases of PCP under belatacept were reported in ABO-incompatible transplantation [1]. A recent study showed that 34/280 patients had presented opportunistic infection after conversion to belatacept, 28.6% represented PJP, i.e. 10 patients about 10 months after conversion to belatacept (50% of early conversion). All these patients were without prophylaxis, and the mortality reached 33.3% [15]. This study also proposed to consider as a risk factor of opportunistic infection the estimated glomerular filtration rate (eGFR) at the time of belatacept conversion: the higher the eGFR, the lower the risk of infection. Even if PJP was documented under belatacept treatment, this treatment alone cannot be fully responsible for the infection of the patient. Indeed a few months after being converted from tacrolimus to belatacept, MMF was replaced by everolimus. It has been reported that everolimus-based therapy can induce interstitial lung diseases (ILD). In a retrospective series of 500 kidney-transplanted patients, Solazzo et al. [16] found 26 ILDs; of these, 12 cases (46.2%) were from infections (42.8% by P. jirovecii), whereas in 14 cases (53.8%) this was related to drug-induced ILD. Finally, there were other facilitating factors such as overimmunosuppression, chronic T-cell lymphopenia, and previous episode of treated acute rejection.
Even though the risk of opportunistic infections resides mostly within the first year post-transplant, the second year after transplantation seems to be still a high-risk period for developing PJP [2]. However, the actual duration of PJP prophylaxis varies between 6 and 12 months post-transplantation; because of this risk within the second year, the duration of prophylaxis should be reevaluated. Goto et al. [17] proposed long-term PJP prophylaxis using TMP-SMX, based on the three outbreaks of PJP they reported in patients who had stopped PJP prophylaxis after 3 months of treatment.
Before considering long-term prophylaxis of PJP using TMP-SMX, it would be helpful to have more data on renal toxicity after long-term exposure to TMP-SMX. Another option could be to conduct studies on reintroduction of PJP prophylaxis after a switch from calcineurin inhibitor-based to belatacept-based therapy. In particular, prophylaxis using a treatment that would not cause renal toxicity, such as monthly aerosol of pentamidine, could be assessed further. Currently, a compromise could be to continue regular biological evaluations in the second year after renal allograft transplantation regarding immunosuppression: lymphocytes, CD4+ T-cell counts, and IgG levels, even if the transplant was ABO and HLA compatible.
Statement of Ethics
Written informed consent for publication (including figures) was obtained from the patient, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Q. Perrier contributed to acquisition of data and writing of the manuscript. R. Tetaz and L. Rostaing provided supervision and mentorship. All the authors approved the final manuscript.
Fig. 1 Bilateral chest X-ray with alveolo-interstitial opacities.
Fig. 2 Evolution of biological markers linked to the management of Pneumocystis jirovecii pneumonia. | BELATACEPT, EVEROLIMUS, LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, SULFAMETHOXAZOLE\TRIMETHOPRIM, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33708795 | 18,975,559 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'No adverse event'. | A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection.
Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that often develops in immunocompromised kidney-allograft recipients [1]. Several risks factors have been described: age, cytomegalovirus (CMV)-positive viremia, neutropenia, a lymphocyte count of <750/mm3 for more than 1 month (although a CD4+ T-cell of <200/µL is not a good biomarker in non-HIV patient), low plasma total gamma globulins, an acute-rejection episode, and immunosuppression treatment [2].
Renal toxicity was previously well described with high dose of trimethoprim-sulfamethoxazole (TMP-SMX) used in PJP treatment, i.e. acute tubular necrosis. SMX acts as a nephrotoxic agent through tubular precipitation and local production of crystal. Renal impermeant was also reported whatever the dose used, i.e. acute interstitial nephritis with immunologically induced hypersensitivity [3, 4]. Therefore, several studies have assessed the use of atovaquone or pentamidine to prevent PJP [5, 6]. Although the results are promising, TMP-SMX is still the first-choice prophylaxis [7]. In fact, the use of TMP-SMX as a prophylactic drug for PJP for 6–12 months after kidney transplantation can significantly decrease its incidence [8].
Herein, this case report describes the management and prevention of PJP in a kidney-allograft recipient receiving maintenance immunosuppressive therapy of belatacept, everolimus, plus corticosteroids.
Case Report
A 49-year-old HLA-sensitized male had end-stage renal disease that was secondary to autosomal dominant polycystic kidney disease, which had first been diagnosed when he was aged 30 years. In 2012, he received peritoneal dialysis for 1 year, and then hemodialysis for 2 years. He then received a kidney transplant in 2015 from a deceased donor. The donor and recipient were both CMV seronegative. The initial induction therapy was based on antithymocyte globulins (Thymoglobulin®, 0.5 mg/kg/day for 5 days) plus a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Serum-creatinine level at 1 month post-transplantation was 194 µmol/L.
At 3 months post-transplantation, serum creatinine had increased to 325 µmol/L, and the histology showed acute cellular rejection, which was treated with 3 boluses of methylprednisolone (10 mg/kg each). Despite the disappearance of inflammatory infiltrates within the interstitium (as seen in a follow-up allograft biopsy), renal function remained altered (creatinine at 319 µmol/L). In January 2017, the patient was converted to a belatacept-based calcineurin-free regimen, which led to recovery of renal function in 18 months: serum-creatinine level became 212 µmol/L. In August 2018, MMF was switched to the antiproliferative drug everolimus because of the risk of developing squamous-cell carcinoma. In December 2018, the patient developed a dry cough with a purulent sputum, although the fever resolved after 7 days of receiving amoxicillin. However, a few days later, he developed progressive and severe dyspnea, which led to his hospitalization 2 weeks later. In a clinical examination, the patient had tachypnea (32 breaths/min), and oxygen saturation was only at 88% in room air. Chest computed tomography showed diffuse bilateral alveolo-interstitial opacities suggesting an opportunistic infection (Fig. 1). The initial blood investigations revealed the following: C-reactive protein, 58 mg/L; low lymphocyte count (0.4 g/L) with no CD4 +T cells detected for 2 years; and hypogammaglobulinemia, i.e. immunoglobulin G (IgG) was 3.2 g/L compared to 4.2 g/L 5 months previously. Legionella, Aspergillus, and Pneumococcusantigenemias, Chlamydia, and Mycoplasma serologies, and a CMV DNAemia were all negative. Samples from a bronchoscopy and a bronchoalveolar lavage were negative for bacterial and viral pathogens (cultures and PCR testing) but revealed a high load of P. jirovecii DNA.
Because of respiratory gravity (i.e., PO2 = 60 mm Hg), the patient was given continuous oxygen support, intravenous corticosteroids (a single dose of 1 mg/kg of methylprednisone, which was then decreased to 0.5 mg/kg), and TMP-SMX (800/160 mg adjusted according to renal function).
After receiving these therapies for 7 days, the patient was weaned off oxygen, and his biological inflammatory markers were improved; however, there was 20% degradation in renal function (shown in Fig. 2). Because of the improved respiratory status but also the renal impairment we converted TMP-SMX to atovaquone for 21 days. The patient could then return home after 9 days of hospitalization with stable renal allograft function (creatinine: 227 µmol/L). Follow-up investigations showed normalization of CRP level, and renal allograft function returned to baseline values (creatinine: 200 µmol/L), and improvements were seen on radiological images. PJP prophylaxis for the next 6 months was pentamidine given as an aerosol monthly in the hospital. Belatacept (5 mg/kg every 4 weeks) was never stopped.
Discussion/Conclusion
At 3 years after renal ABO- and HLA-compatible allograft, and 2 years after conversion from tacrolimus to belatacept, our patient had developed acute PJP. He had presented several risks factors: immunosuppressive treatment (belatacept and everolimus), history of acute cellular rejection at 3 months post-transplantation, biological evidence of overimmunosuppression, i.e. low lymphocyte count with no CD4 T cell and decrease in IgG at 3.2 g/L. Indeed, antithymocyte globulins result in long-term lymphopenia. Crepin et al. [9] have reported that ATG delays thymic-dependent T cell reconstitution, increases the frequency of late-stage differentiated T cells, and promotes peripheral Treg expansion. Moreover, ATG is associated with persistent low values of T-cell relative telomere length and telomerase activity. Taken together, these data suggest that ATG induces accelerated immune senescence.
Hughes et al. [10] compared treating acute PJP with atovaquone or TMP-SMX. Patients treated with atovaquone “more often had no response” and had a higher mortality rate (7 vs. 0.6%, p = 0.003). Thus, TMP-SMX was the first treatment recommended to treat acute PJP [7]. At admission, our patient presented with acute-phase PJP with gravity criteria (he needed oxygen: PO2 = 60 mm Hg): at that time, the benefit-risk balance favored an aggressive induction treatment. Nevertheless, after 1 week, the benefit-risk balance became reversed in favor of preserving renal function according to respiratory improvement status. Thus, our patient was switched to receive atovaquone instead. After the induction treatment, he received pentamidine as the prophylaxis.
Belatacept, a new costimulation blocker has attracted interest as a treatment to preserve renal function, and improved cardiovascular/metabolic risk profile without infectious alarm signal confirmed by Vicenti and al. [11] after 7 years of use. Specific studies about early [12] or late [13] conversion to belatacept did not report PJP. The first case of lethal PCP under belatacept was described by Haidinger et al. [14] 4 years after transplantation in a multi-infected patient. Then, three other cases of PCP under belatacept were reported in ABO-incompatible transplantation [1]. A recent study showed that 34/280 patients had presented opportunistic infection after conversion to belatacept, 28.6% represented PJP, i.e. 10 patients about 10 months after conversion to belatacept (50% of early conversion). All these patients were without prophylaxis, and the mortality reached 33.3% [15]. This study also proposed to consider as a risk factor of opportunistic infection the estimated glomerular filtration rate (eGFR) at the time of belatacept conversion: the higher the eGFR, the lower the risk of infection. Even if PJP was documented under belatacept treatment, this treatment alone cannot be fully responsible for the infection of the patient. Indeed a few months after being converted from tacrolimus to belatacept, MMF was replaced by everolimus. It has been reported that everolimus-based therapy can induce interstitial lung diseases (ILD). In a retrospective series of 500 kidney-transplanted patients, Solazzo et al. [16] found 26 ILDs; of these, 12 cases (46.2%) were from infections (42.8% by P. jirovecii), whereas in 14 cases (53.8%) this was related to drug-induced ILD. Finally, there were other facilitating factors such as overimmunosuppression, chronic T-cell lymphopenia, and previous episode of treated acute rejection.
Even though the risk of opportunistic infections resides mostly within the first year post-transplant, the second year after transplantation seems to be still a high-risk period for developing PJP [2]. However, the actual duration of PJP prophylaxis varies between 6 and 12 months post-transplantation; because of this risk within the second year, the duration of prophylaxis should be reevaluated. Goto et al. [17] proposed long-term PJP prophylaxis using TMP-SMX, based on the three outbreaks of PJP they reported in patients who had stopped PJP prophylaxis after 3 months of treatment.
Before considering long-term prophylaxis of PJP using TMP-SMX, it would be helpful to have more data on renal toxicity after long-term exposure to TMP-SMX. Another option could be to conduct studies on reintroduction of PJP prophylaxis after a switch from calcineurin inhibitor-based to belatacept-based therapy. In particular, prophylaxis using a treatment that would not cause renal toxicity, such as monthly aerosol of pentamidine, could be assessed further. Currently, a compromise could be to continue regular biological evaluations in the second year after renal allograft transplantation regarding immunosuppression: lymphocytes, CD4+ T-cell counts, and IgG levels, even if the transplant was ABO and HLA compatible.
Statement of Ethics
Written informed consent for publication (including figures) was obtained from the patient, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Q. Perrier contributed to acquisition of data and writing of the manuscript. R. Tetaz and L. Rostaing provided supervision and mentorship. All the authors approved the final manuscript.
Fig. 1 Bilateral chest X-ray with alveolo-interstitial opacities.
Fig. 2 Evolution of biological markers linked to the management of Pneumocystis jirovecii pneumonia. | BELATACEPT, EVEROLIMUS, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL | DrugsGivenReaction | CC BY-NC | 33708795 | 19,019,328 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection.
Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that often develops in immunocompromised kidney-allograft recipients [1]. Several risks factors have been described: age, cytomegalovirus (CMV)-positive viremia, neutropenia, a lymphocyte count of <750/mm3 for more than 1 month (although a CD4+ T-cell of <200/µL is not a good biomarker in non-HIV patient), low plasma total gamma globulins, an acute-rejection episode, and immunosuppression treatment [2].
Renal toxicity was previously well described with high dose of trimethoprim-sulfamethoxazole (TMP-SMX) used in PJP treatment, i.e. acute tubular necrosis. SMX acts as a nephrotoxic agent through tubular precipitation and local production of crystal. Renal impermeant was also reported whatever the dose used, i.e. acute interstitial nephritis with immunologically induced hypersensitivity [3, 4]. Therefore, several studies have assessed the use of atovaquone or pentamidine to prevent PJP [5, 6]. Although the results are promising, TMP-SMX is still the first-choice prophylaxis [7]. In fact, the use of TMP-SMX as a prophylactic drug for PJP for 6–12 months after kidney transplantation can significantly decrease its incidence [8].
Herein, this case report describes the management and prevention of PJP in a kidney-allograft recipient receiving maintenance immunosuppressive therapy of belatacept, everolimus, plus corticosteroids.
Case Report
A 49-year-old HLA-sensitized male had end-stage renal disease that was secondary to autosomal dominant polycystic kidney disease, which had first been diagnosed when he was aged 30 years. In 2012, he received peritoneal dialysis for 1 year, and then hemodialysis for 2 years. He then received a kidney transplant in 2015 from a deceased donor. The donor and recipient were both CMV seronegative. The initial induction therapy was based on antithymocyte globulins (Thymoglobulin®, 0.5 mg/kg/day for 5 days) plus a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Serum-creatinine level at 1 month post-transplantation was 194 µmol/L.
At 3 months post-transplantation, serum creatinine had increased to 325 µmol/L, and the histology showed acute cellular rejection, which was treated with 3 boluses of methylprednisolone (10 mg/kg each). Despite the disappearance of inflammatory infiltrates within the interstitium (as seen in a follow-up allograft biopsy), renal function remained altered (creatinine at 319 µmol/L). In January 2017, the patient was converted to a belatacept-based calcineurin-free regimen, which led to recovery of renal function in 18 months: serum-creatinine level became 212 µmol/L. In August 2018, MMF was switched to the antiproliferative drug everolimus because of the risk of developing squamous-cell carcinoma. In December 2018, the patient developed a dry cough with a purulent sputum, although the fever resolved after 7 days of receiving amoxicillin. However, a few days later, he developed progressive and severe dyspnea, which led to his hospitalization 2 weeks later. In a clinical examination, the patient had tachypnea (32 breaths/min), and oxygen saturation was only at 88% in room air. Chest computed tomography showed diffuse bilateral alveolo-interstitial opacities suggesting an opportunistic infection (Fig. 1). The initial blood investigations revealed the following: C-reactive protein, 58 mg/L; low lymphocyte count (0.4 g/L) with no CD4 +T cells detected for 2 years; and hypogammaglobulinemia, i.e. immunoglobulin G (IgG) was 3.2 g/L compared to 4.2 g/L 5 months previously. Legionella, Aspergillus, and Pneumococcusantigenemias, Chlamydia, and Mycoplasma serologies, and a CMV DNAemia were all negative. Samples from a bronchoscopy and a bronchoalveolar lavage were negative for bacterial and viral pathogens (cultures and PCR testing) but revealed a high load of P. jirovecii DNA.
Because of respiratory gravity (i.e., PO2 = 60 mm Hg), the patient was given continuous oxygen support, intravenous corticosteroids (a single dose of 1 mg/kg of methylprednisone, which was then decreased to 0.5 mg/kg), and TMP-SMX (800/160 mg adjusted according to renal function).
After receiving these therapies for 7 days, the patient was weaned off oxygen, and his biological inflammatory markers were improved; however, there was 20% degradation in renal function (shown in Fig. 2). Because of the improved respiratory status but also the renal impairment we converted TMP-SMX to atovaquone for 21 days. The patient could then return home after 9 days of hospitalization with stable renal allograft function (creatinine: 227 µmol/L). Follow-up investigations showed normalization of CRP level, and renal allograft function returned to baseline values (creatinine: 200 µmol/L), and improvements were seen on radiological images. PJP prophylaxis for the next 6 months was pentamidine given as an aerosol monthly in the hospital. Belatacept (5 mg/kg every 4 weeks) was never stopped.
Discussion/Conclusion
At 3 years after renal ABO- and HLA-compatible allograft, and 2 years after conversion from tacrolimus to belatacept, our patient had developed acute PJP. He had presented several risks factors: immunosuppressive treatment (belatacept and everolimus), history of acute cellular rejection at 3 months post-transplantation, biological evidence of overimmunosuppression, i.e. low lymphocyte count with no CD4 T cell and decrease in IgG at 3.2 g/L. Indeed, antithymocyte globulins result in long-term lymphopenia. Crepin et al. [9] have reported that ATG delays thymic-dependent T cell reconstitution, increases the frequency of late-stage differentiated T cells, and promotes peripheral Treg expansion. Moreover, ATG is associated with persistent low values of T-cell relative telomere length and telomerase activity. Taken together, these data suggest that ATG induces accelerated immune senescence.
Hughes et al. [10] compared treating acute PJP with atovaquone or TMP-SMX. Patients treated with atovaquone “more often had no response” and had a higher mortality rate (7 vs. 0.6%, p = 0.003). Thus, TMP-SMX was the first treatment recommended to treat acute PJP [7]. At admission, our patient presented with acute-phase PJP with gravity criteria (he needed oxygen: PO2 = 60 mm Hg): at that time, the benefit-risk balance favored an aggressive induction treatment. Nevertheless, after 1 week, the benefit-risk balance became reversed in favor of preserving renal function according to respiratory improvement status. Thus, our patient was switched to receive atovaquone instead. After the induction treatment, he received pentamidine as the prophylaxis.
Belatacept, a new costimulation blocker has attracted interest as a treatment to preserve renal function, and improved cardiovascular/metabolic risk profile without infectious alarm signal confirmed by Vicenti and al. [11] after 7 years of use. Specific studies about early [12] or late [13] conversion to belatacept did not report PJP. The first case of lethal PCP under belatacept was described by Haidinger et al. [14] 4 years after transplantation in a multi-infected patient. Then, three other cases of PCP under belatacept were reported in ABO-incompatible transplantation [1]. A recent study showed that 34/280 patients had presented opportunistic infection after conversion to belatacept, 28.6% represented PJP, i.e. 10 patients about 10 months after conversion to belatacept (50% of early conversion). All these patients were without prophylaxis, and the mortality reached 33.3% [15]. This study also proposed to consider as a risk factor of opportunistic infection the estimated glomerular filtration rate (eGFR) at the time of belatacept conversion: the higher the eGFR, the lower the risk of infection. Even if PJP was documented under belatacept treatment, this treatment alone cannot be fully responsible for the infection of the patient. Indeed a few months after being converted from tacrolimus to belatacept, MMF was replaced by everolimus. It has been reported that everolimus-based therapy can induce interstitial lung diseases (ILD). In a retrospective series of 500 kidney-transplanted patients, Solazzo et al. [16] found 26 ILDs; of these, 12 cases (46.2%) were from infections (42.8% by P. jirovecii), whereas in 14 cases (53.8%) this was related to drug-induced ILD. Finally, there were other facilitating factors such as overimmunosuppression, chronic T-cell lymphopenia, and previous episode of treated acute rejection.
Even though the risk of opportunistic infections resides mostly within the first year post-transplant, the second year after transplantation seems to be still a high-risk period for developing PJP [2]. However, the actual duration of PJP prophylaxis varies between 6 and 12 months post-transplantation; because of this risk within the second year, the duration of prophylaxis should be reevaluated. Goto et al. [17] proposed long-term PJP prophylaxis using TMP-SMX, based on the three outbreaks of PJP they reported in patients who had stopped PJP prophylaxis after 3 months of treatment.
Before considering long-term prophylaxis of PJP using TMP-SMX, it would be helpful to have more data on renal toxicity after long-term exposure to TMP-SMX. Another option could be to conduct studies on reintroduction of PJP prophylaxis after a switch from calcineurin inhibitor-based to belatacept-based therapy. In particular, prophylaxis using a treatment that would not cause renal toxicity, such as monthly aerosol of pentamidine, could be assessed further. Currently, a compromise could be to continue regular biological evaluations in the second year after renal allograft transplantation regarding immunosuppression: lymphocytes, CD4+ T-cell counts, and IgG levels, even if the transplant was ABO and HLA compatible.
Statement of Ethics
Written informed consent for publication (including figures) was obtained from the patient, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Q. Perrier contributed to acquisition of data and writing of the manuscript. R. Tetaz and L. Rostaing provided supervision and mentorship. All the authors approved the final manuscript.
Fig. 1 Bilateral chest X-ray with alveolo-interstitial opacities.
Fig. 2 Evolution of biological markers linked to the management of Pneumocystis jirovecii pneumonia. | BELATACEPT, EVEROLIMUS, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL | DrugsGivenReaction | CC BY-NC | 33708795 | 18,957,732 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Transplant rejection'. | A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection.
Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that often develops in immunocompromised kidney-allograft recipients [1]. Several risks factors have been described: age, cytomegalovirus (CMV)-positive viremia, neutropenia, a lymphocyte count of <750/mm3 for more than 1 month (although a CD4+ T-cell of <200/µL is not a good biomarker in non-HIV patient), low plasma total gamma globulins, an acute-rejection episode, and immunosuppression treatment [2].
Renal toxicity was previously well described with high dose of trimethoprim-sulfamethoxazole (TMP-SMX) used in PJP treatment, i.e. acute tubular necrosis. SMX acts as a nephrotoxic agent through tubular precipitation and local production of crystal. Renal impermeant was also reported whatever the dose used, i.e. acute interstitial nephritis with immunologically induced hypersensitivity [3, 4]. Therefore, several studies have assessed the use of atovaquone or pentamidine to prevent PJP [5, 6]. Although the results are promising, TMP-SMX is still the first-choice prophylaxis [7]. In fact, the use of TMP-SMX as a prophylactic drug for PJP for 6–12 months after kidney transplantation can significantly decrease its incidence [8].
Herein, this case report describes the management and prevention of PJP in a kidney-allograft recipient receiving maintenance immunosuppressive therapy of belatacept, everolimus, plus corticosteroids.
Case Report
A 49-year-old HLA-sensitized male had end-stage renal disease that was secondary to autosomal dominant polycystic kidney disease, which had first been diagnosed when he was aged 30 years. In 2012, he received peritoneal dialysis for 1 year, and then hemodialysis for 2 years. He then received a kidney transplant in 2015 from a deceased donor. The donor and recipient were both CMV seronegative. The initial induction therapy was based on antithymocyte globulins (Thymoglobulin®, 0.5 mg/kg/day for 5 days) plus a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Serum-creatinine level at 1 month post-transplantation was 194 µmol/L.
At 3 months post-transplantation, serum creatinine had increased to 325 µmol/L, and the histology showed acute cellular rejection, which was treated with 3 boluses of methylprednisolone (10 mg/kg each). Despite the disappearance of inflammatory infiltrates within the interstitium (as seen in a follow-up allograft biopsy), renal function remained altered (creatinine at 319 µmol/L). In January 2017, the patient was converted to a belatacept-based calcineurin-free regimen, which led to recovery of renal function in 18 months: serum-creatinine level became 212 µmol/L. In August 2018, MMF was switched to the antiproliferative drug everolimus because of the risk of developing squamous-cell carcinoma. In December 2018, the patient developed a dry cough with a purulent sputum, although the fever resolved after 7 days of receiving amoxicillin. However, a few days later, he developed progressive and severe dyspnea, which led to his hospitalization 2 weeks later. In a clinical examination, the patient had tachypnea (32 breaths/min), and oxygen saturation was only at 88% in room air. Chest computed tomography showed diffuse bilateral alveolo-interstitial opacities suggesting an opportunistic infection (Fig. 1). The initial blood investigations revealed the following: C-reactive protein, 58 mg/L; low lymphocyte count (0.4 g/L) with no CD4 +T cells detected for 2 years; and hypogammaglobulinemia, i.e. immunoglobulin G (IgG) was 3.2 g/L compared to 4.2 g/L 5 months previously. Legionella, Aspergillus, and Pneumococcusantigenemias, Chlamydia, and Mycoplasma serologies, and a CMV DNAemia were all negative. Samples from a bronchoscopy and a bronchoalveolar lavage were negative for bacterial and viral pathogens (cultures and PCR testing) but revealed a high load of P. jirovecii DNA.
Because of respiratory gravity (i.e., PO2 = 60 mm Hg), the patient was given continuous oxygen support, intravenous corticosteroids (a single dose of 1 mg/kg of methylprednisone, which was then decreased to 0.5 mg/kg), and TMP-SMX (800/160 mg adjusted according to renal function).
After receiving these therapies for 7 days, the patient was weaned off oxygen, and his biological inflammatory markers were improved; however, there was 20% degradation in renal function (shown in Fig. 2). Because of the improved respiratory status but also the renal impairment we converted TMP-SMX to atovaquone for 21 days. The patient could then return home after 9 days of hospitalization with stable renal allograft function (creatinine: 227 µmol/L). Follow-up investigations showed normalization of CRP level, and renal allograft function returned to baseline values (creatinine: 200 µmol/L), and improvements were seen on radiological images. PJP prophylaxis for the next 6 months was pentamidine given as an aerosol monthly in the hospital. Belatacept (5 mg/kg every 4 weeks) was never stopped.
Discussion/Conclusion
At 3 years after renal ABO- and HLA-compatible allograft, and 2 years after conversion from tacrolimus to belatacept, our patient had developed acute PJP. He had presented several risks factors: immunosuppressive treatment (belatacept and everolimus), history of acute cellular rejection at 3 months post-transplantation, biological evidence of overimmunosuppression, i.e. low lymphocyte count with no CD4 T cell and decrease in IgG at 3.2 g/L. Indeed, antithymocyte globulins result in long-term lymphopenia. Crepin et al. [9] have reported that ATG delays thymic-dependent T cell reconstitution, increases the frequency of late-stage differentiated T cells, and promotes peripheral Treg expansion. Moreover, ATG is associated with persistent low values of T-cell relative telomere length and telomerase activity. Taken together, these data suggest that ATG induces accelerated immune senescence.
Hughes et al. [10] compared treating acute PJP with atovaquone or TMP-SMX. Patients treated with atovaquone “more often had no response” and had a higher mortality rate (7 vs. 0.6%, p = 0.003). Thus, TMP-SMX was the first treatment recommended to treat acute PJP [7]. At admission, our patient presented with acute-phase PJP with gravity criteria (he needed oxygen: PO2 = 60 mm Hg): at that time, the benefit-risk balance favored an aggressive induction treatment. Nevertheless, after 1 week, the benefit-risk balance became reversed in favor of preserving renal function according to respiratory improvement status. Thus, our patient was switched to receive atovaquone instead. After the induction treatment, he received pentamidine as the prophylaxis.
Belatacept, a new costimulation blocker has attracted interest as a treatment to preserve renal function, and improved cardiovascular/metabolic risk profile without infectious alarm signal confirmed by Vicenti and al. [11] after 7 years of use. Specific studies about early [12] or late [13] conversion to belatacept did not report PJP. The first case of lethal PCP under belatacept was described by Haidinger et al. [14] 4 years after transplantation in a multi-infected patient. Then, three other cases of PCP under belatacept were reported in ABO-incompatible transplantation [1]. A recent study showed that 34/280 patients had presented opportunistic infection after conversion to belatacept, 28.6% represented PJP, i.e. 10 patients about 10 months after conversion to belatacept (50% of early conversion). All these patients were without prophylaxis, and the mortality reached 33.3% [15]. This study also proposed to consider as a risk factor of opportunistic infection the estimated glomerular filtration rate (eGFR) at the time of belatacept conversion: the higher the eGFR, the lower the risk of infection. Even if PJP was documented under belatacept treatment, this treatment alone cannot be fully responsible for the infection of the patient. Indeed a few months after being converted from tacrolimus to belatacept, MMF was replaced by everolimus. It has been reported that everolimus-based therapy can induce interstitial lung diseases (ILD). In a retrospective series of 500 kidney-transplanted patients, Solazzo et al. [16] found 26 ILDs; of these, 12 cases (46.2%) were from infections (42.8% by P. jirovecii), whereas in 14 cases (53.8%) this was related to drug-induced ILD. Finally, there were other facilitating factors such as overimmunosuppression, chronic T-cell lymphopenia, and previous episode of treated acute rejection.
Even though the risk of opportunistic infections resides mostly within the first year post-transplant, the second year after transplantation seems to be still a high-risk period for developing PJP [2]. However, the actual duration of PJP prophylaxis varies between 6 and 12 months post-transplantation; because of this risk within the second year, the duration of prophylaxis should be reevaluated. Goto et al. [17] proposed long-term PJP prophylaxis using TMP-SMX, based on the three outbreaks of PJP they reported in patients who had stopped PJP prophylaxis after 3 months of treatment.
Before considering long-term prophylaxis of PJP using TMP-SMX, it would be helpful to have more data on renal toxicity after long-term exposure to TMP-SMX. Another option could be to conduct studies on reintroduction of PJP prophylaxis after a switch from calcineurin inhibitor-based to belatacept-based therapy. In particular, prophylaxis using a treatment that would not cause renal toxicity, such as monthly aerosol of pentamidine, could be assessed further. Currently, a compromise could be to continue regular biological evaluations in the second year after renal allograft transplantation regarding immunosuppression: lymphocytes, CD4+ T-cell counts, and IgG levels, even if the transplant was ABO and HLA compatible.
Statement of Ethics
Written informed consent for publication (including figures) was obtained from the patient, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Q. Perrier contributed to acquisition of data and writing of the manuscript. R. Tetaz and L. Rostaing provided supervision and mentorship. All the authors approved the final manuscript.
Fig. 1 Bilateral chest X-ray with alveolo-interstitial opacities.
Fig. 2 Evolution of biological markers linked to the management of Pneumocystis jirovecii pneumonia. | LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33708795 | 19,071,017 | 2021 |
What is the weight of the patient? | A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection.
Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that often develops in immunocompromised kidney-allograft recipients [1]. Several risks factors have been described: age, cytomegalovirus (CMV)-positive viremia, neutropenia, a lymphocyte count of <750/mm3 for more than 1 month (although a CD4+ T-cell of <200/µL is not a good biomarker in non-HIV patient), low plasma total gamma globulins, an acute-rejection episode, and immunosuppression treatment [2].
Renal toxicity was previously well described with high dose of trimethoprim-sulfamethoxazole (TMP-SMX) used in PJP treatment, i.e. acute tubular necrosis. SMX acts as a nephrotoxic agent through tubular precipitation and local production of crystal. Renal impermeant was also reported whatever the dose used, i.e. acute interstitial nephritis with immunologically induced hypersensitivity [3, 4]. Therefore, several studies have assessed the use of atovaquone or pentamidine to prevent PJP [5, 6]. Although the results are promising, TMP-SMX is still the first-choice prophylaxis [7]. In fact, the use of TMP-SMX as a prophylactic drug for PJP for 6–12 months after kidney transplantation can significantly decrease its incidence [8].
Herein, this case report describes the management and prevention of PJP in a kidney-allograft recipient receiving maintenance immunosuppressive therapy of belatacept, everolimus, plus corticosteroids.
Case Report
A 49-year-old HLA-sensitized male had end-stage renal disease that was secondary to autosomal dominant polycystic kidney disease, which had first been diagnosed when he was aged 30 years. In 2012, he received peritoneal dialysis for 1 year, and then hemodialysis for 2 years. He then received a kidney transplant in 2015 from a deceased donor. The donor and recipient were both CMV seronegative. The initial induction therapy was based on antithymocyte globulins (Thymoglobulin®, 0.5 mg/kg/day for 5 days) plus a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Serum-creatinine level at 1 month post-transplantation was 194 µmol/L.
At 3 months post-transplantation, serum creatinine had increased to 325 µmol/L, and the histology showed acute cellular rejection, which was treated with 3 boluses of methylprednisolone (10 mg/kg each). Despite the disappearance of inflammatory infiltrates within the interstitium (as seen in a follow-up allograft biopsy), renal function remained altered (creatinine at 319 µmol/L). In January 2017, the patient was converted to a belatacept-based calcineurin-free regimen, which led to recovery of renal function in 18 months: serum-creatinine level became 212 µmol/L. In August 2018, MMF was switched to the antiproliferative drug everolimus because of the risk of developing squamous-cell carcinoma. In December 2018, the patient developed a dry cough with a purulent sputum, although the fever resolved after 7 days of receiving amoxicillin. However, a few days later, he developed progressive and severe dyspnea, which led to his hospitalization 2 weeks later. In a clinical examination, the patient had tachypnea (32 breaths/min), and oxygen saturation was only at 88% in room air. Chest computed tomography showed diffuse bilateral alveolo-interstitial opacities suggesting an opportunistic infection (Fig. 1). The initial blood investigations revealed the following: C-reactive protein, 58 mg/L; low lymphocyte count (0.4 g/L) with no CD4 +T cells detected for 2 years; and hypogammaglobulinemia, i.e. immunoglobulin G (IgG) was 3.2 g/L compared to 4.2 g/L 5 months previously. Legionella, Aspergillus, and Pneumococcusantigenemias, Chlamydia, and Mycoplasma serologies, and a CMV DNAemia were all negative. Samples from a bronchoscopy and a bronchoalveolar lavage were negative for bacterial and viral pathogens (cultures and PCR testing) but revealed a high load of P. jirovecii DNA.
Because of respiratory gravity (i.e., PO2 = 60 mm Hg), the patient was given continuous oxygen support, intravenous corticosteroids (a single dose of 1 mg/kg of methylprednisone, which was then decreased to 0.5 mg/kg), and TMP-SMX (800/160 mg adjusted according to renal function).
After receiving these therapies for 7 days, the patient was weaned off oxygen, and his biological inflammatory markers were improved; however, there was 20% degradation in renal function (shown in Fig. 2). Because of the improved respiratory status but also the renal impairment we converted TMP-SMX to atovaquone for 21 days. The patient could then return home after 9 days of hospitalization with stable renal allograft function (creatinine: 227 µmol/L). Follow-up investigations showed normalization of CRP level, and renal allograft function returned to baseline values (creatinine: 200 µmol/L), and improvements were seen on radiological images. PJP prophylaxis for the next 6 months was pentamidine given as an aerosol monthly in the hospital. Belatacept (5 mg/kg every 4 weeks) was never stopped.
Discussion/Conclusion
At 3 years after renal ABO- and HLA-compatible allograft, and 2 years after conversion from tacrolimus to belatacept, our patient had developed acute PJP. He had presented several risks factors: immunosuppressive treatment (belatacept and everolimus), history of acute cellular rejection at 3 months post-transplantation, biological evidence of overimmunosuppression, i.e. low lymphocyte count with no CD4 T cell and decrease in IgG at 3.2 g/L. Indeed, antithymocyte globulins result in long-term lymphopenia. Crepin et al. [9] have reported that ATG delays thymic-dependent T cell reconstitution, increases the frequency of late-stage differentiated T cells, and promotes peripheral Treg expansion. Moreover, ATG is associated with persistent low values of T-cell relative telomere length and telomerase activity. Taken together, these data suggest that ATG induces accelerated immune senescence.
Hughes et al. [10] compared treating acute PJP with atovaquone or TMP-SMX. Patients treated with atovaquone “more often had no response” and had a higher mortality rate (7 vs. 0.6%, p = 0.003). Thus, TMP-SMX was the first treatment recommended to treat acute PJP [7]. At admission, our patient presented with acute-phase PJP with gravity criteria (he needed oxygen: PO2 = 60 mm Hg): at that time, the benefit-risk balance favored an aggressive induction treatment. Nevertheless, after 1 week, the benefit-risk balance became reversed in favor of preserving renal function according to respiratory improvement status. Thus, our patient was switched to receive atovaquone instead. After the induction treatment, he received pentamidine as the prophylaxis.
Belatacept, a new costimulation blocker has attracted interest as a treatment to preserve renal function, and improved cardiovascular/metabolic risk profile without infectious alarm signal confirmed by Vicenti and al. [11] after 7 years of use. Specific studies about early [12] or late [13] conversion to belatacept did not report PJP. The first case of lethal PCP under belatacept was described by Haidinger et al. [14] 4 years after transplantation in a multi-infected patient. Then, three other cases of PCP under belatacept were reported in ABO-incompatible transplantation [1]. A recent study showed that 34/280 patients had presented opportunistic infection after conversion to belatacept, 28.6% represented PJP, i.e. 10 patients about 10 months after conversion to belatacept (50% of early conversion). All these patients were without prophylaxis, and the mortality reached 33.3% [15]. This study also proposed to consider as a risk factor of opportunistic infection the estimated glomerular filtration rate (eGFR) at the time of belatacept conversion: the higher the eGFR, the lower the risk of infection. Even if PJP was documented under belatacept treatment, this treatment alone cannot be fully responsible for the infection of the patient. Indeed a few months after being converted from tacrolimus to belatacept, MMF was replaced by everolimus. It has been reported that everolimus-based therapy can induce interstitial lung diseases (ILD). In a retrospective series of 500 kidney-transplanted patients, Solazzo et al. [16] found 26 ILDs; of these, 12 cases (46.2%) were from infections (42.8% by P. jirovecii), whereas in 14 cases (53.8%) this was related to drug-induced ILD. Finally, there were other facilitating factors such as overimmunosuppression, chronic T-cell lymphopenia, and previous episode of treated acute rejection.
Even though the risk of opportunistic infections resides mostly within the first year post-transplant, the second year after transplantation seems to be still a high-risk period for developing PJP [2]. However, the actual duration of PJP prophylaxis varies between 6 and 12 months post-transplantation; because of this risk within the second year, the duration of prophylaxis should be reevaluated. Goto et al. [17] proposed long-term PJP prophylaxis using TMP-SMX, based on the three outbreaks of PJP they reported in patients who had stopped PJP prophylaxis after 3 months of treatment.
Before considering long-term prophylaxis of PJP using TMP-SMX, it would be helpful to have more data on renal toxicity after long-term exposure to TMP-SMX. Another option could be to conduct studies on reintroduction of PJP prophylaxis after a switch from calcineurin inhibitor-based to belatacept-based therapy. In particular, prophylaxis using a treatment that would not cause renal toxicity, such as monthly aerosol of pentamidine, could be assessed further. Currently, a compromise could be to continue regular biological evaluations in the second year after renal allograft transplantation regarding immunosuppression: lymphocytes, CD4+ T-cell counts, and IgG levels, even if the transplant was ABO and HLA compatible.
Statement of Ethics
Written informed consent for publication (including figures) was obtained from the patient, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Q. Perrier contributed to acquisition of data and writing of the manuscript. R. Tetaz and L. Rostaing provided supervision and mentorship. All the authors approved the final manuscript.
Fig. 1 Bilateral chest X-ray with alveolo-interstitial opacities.
Fig. 2 Evolution of biological markers linked to the management of Pneumocystis jirovecii pneumonia. | 83 kg. | Weight | CC BY-NC | 33708795 | 18,957,732 | 2021 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection.
Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that often develops in immunocompromised kidney-allograft recipients [1]. Several risks factors have been described: age, cytomegalovirus (CMV)-positive viremia, neutropenia, a lymphocyte count of <750/mm3 for more than 1 month (although a CD4+ T-cell of <200/µL is not a good biomarker in non-HIV patient), low plasma total gamma globulins, an acute-rejection episode, and immunosuppression treatment [2].
Renal toxicity was previously well described with high dose of trimethoprim-sulfamethoxazole (TMP-SMX) used in PJP treatment, i.e. acute tubular necrosis. SMX acts as a nephrotoxic agent through tubular precipitation and local production of crystal. Renal impermeant was also reported whatever the dose used, i.e. acute interstitial nephritis with immunologically induced hypersensitivity [3, 4]. Therefore, several studies have assessed the use of atovaquone or pentamidine to prevent PJP [5, 6]. Although the results are promising, TMP-SMX is still the first-choice prophylaxis [7]. In fact, the use of TMP-SMX as a prophylactic drug for PJP for 6–12 months after kidney transplantation can significantly decrease its incidence [8].
Herein, this case report describes the management and prevention of PJP in a kidney-allograft recipient receiving maintenance immunosuppressive therapy of belatacept, everolimus, plus corticosteroids.
Case Report
A 49-year-old HLA-sensitized male had end-stage renal disease that was secondary to autosomal dominant polycystic kidney disease, which had first been diagnosed when he was aged 30 years. In 2012, he received peritoneal dialysis for 1 year, and then hemodialysis for 2 years. He then received a kidney transplant in 2015 from a deceased donor. The donor and recipient were both CMV seronegative. The initial induction therapy was based on antithymocyte globulins (Thymoglobulin®, 0.5 mg/kg/day for 5 days) plus a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Serum-creatinine level at 1 month post-transplantation was 194 µmol/L.
At 3 months post-transplantation, serum creatinine had increased to 325 µmol/L, and the histology showed acute cellular rejection, which was treated with 3 boluses of methylprednisolone (10 mg/kg each). Despite the disappearance of inflammatory infiltrates within the interstitium (as seen in a follow-up allograft biopsy), renal function remained altered (creatinine at 319 µmol/L). In January 2017, the patient was converted to a belatacept-based calcineurin-free regimen, which led to recovery of renal function in 18 months: serum-creatinine level became 212 µmol/L. In August 2018, MMF was switched to the antiproliferative drug everolimus because of the risk of developing squamous-cell carcinoma. In December 2018, the patient developed a dry cough with a purulent sputum, although the fever resolved after 7 days of receiving amoxicillin. However, a few days later, he developed progressive and severe dyspnea, which led to his hospitalization 2 weeks later. In a clinical examination, the patient had tachypnea (32 breaths/min), and oxygen saturation was only at 88% in room air. Chest computed tomography showed diffuse bilateral alveolo-interstitial opacities suggesting an opportunistic infection (Fig. 1). The initial blood investigations revealed the following: C-reactive protein, 58 mg/L; low lymphocyte count (0.4 g/L) with no CD4 +T cells detected for 2 years; and hypogammaglobulinemia, i.e. immunoglobulin G (IgG) was 3.2 g/L compared to 4.2 g/L 5 months previously. Legionella, Aspergillus, and Pneumococcusantigenemias, Chlamydia, and Mycoplasma serologies, and a CMV DNAemia were all negative. Samples from a bronchoscopy and a bronchoalveolar lavage were negative for bacterial and viral pathogens (cultures and PCR testing) but revealed a high load of P. jirovecii DNA.
Because of respiratory gravity (i.e., PO2 = 60 mm Hg), the patient was given continuous oxygen support, intravenous corticosteroids (a single dose of 1 mg/kg of methylprednisone, which was then decreased to 0.5 mg/kg), and TMP-SMX (800/160 mg adjusted according to renal function).
After receiving these therapies for 7 days, the patient was weaned off oxygen, and his biological inflammatory markers were improved; however, there was 20% degradation in renal function (shown in Fig. 2). Because of the improved respiratory status but also the renal impairment we converted TMP-SMX to atovaquone for 21 days. The patient could then return home after 9 days of hospitalization with stable renal allograft function (creatinine: 227 µmol/L). Follow-up investigations showed normalization of CRP level, and renal allograft function returned to baseline values (creatinine: 200 µmol/L), and improvements were seen on radiological images. PJP prophylaxis for the next 6 months was pentamidine given as an aerosol monthly in the hospital. Belatacept (5 mg/kg every 4 weeks) was never stopped.
Discussion/Conclusion
At 3 years after renal ABO- and HLA-compatible allograft, and 2 years after conversion from tacrolimus to belatacept, our patient had developed acute PJP. He had presented several risks factors: immunosuppressive treatment (belatacept and everolimus), history of acute cellular rejection at 3 months post-transplantation, biological evidence of overimmunosuppression, i.e. low lymphocyte count with no CD4 T cell and decrease in IgG at 3.2 g/L. Indeed, antithymocyte globulins result in long-term lymphopenia. Crepin et al. [9] have reported that ATG delays thymic-dependent T cell reconstitution, increases the frequency of late-stage differentiated T cells, and promotes peripheral Treg expansion. Moreover, ATG is associated with persistent low values of T-cell relative telomere length and telomerase activity. Taken together, these data suggest that ATG induces accelerated immune senescence.
Hughes et al. [10] compared treating acute PJP with atovaquone or TMP-SMX. Patients treated with atovaquone “more often had no response” and had a higher mortality rate (7 vs. 0.6%, p = 0.003). Thus, TMP-SMX was the first treatment recommended to treat acute PJP [7]. At admission, our patient presented with acute-phase PJP with gravity criteria (he needed oxygen: PO2 = 60 mm Hg): at that time, the benefit-risk balance favored an aggressive induction treatment. Nevertheless, after 1 week, the benefit-risk balance became reversed in favor of preserving renal function according to respiratory improvement status. Thus, our patient was switched to receive atovaquone instead. After the induction treatment, he received pentamidine as the prophylaxis.
Belatacept, a new costimulation blocker has attracted interest as a treatment to preserve renal function, and improved cardiovascular/metabolic risk profile without infectious alarm signal confirmed by Vicenti and al. [11] after 7 years of use. Specific studies about early [12] or late [13] conversion to belatacept did not report PJP. The first case of lethal PCP under belatacept was described by Haidinger et al. [14] 4 years after transplantation in a multi-infected patient. Then, three other cases of PCP under belatacept were reported in ABO-incompatible transplantation [1]. A recent study showed that 34/280 patients had presented opportunistic infection after conversion to belatacept, 28.6% represented PJP, i.e. 10 patients about 10 months after conversion to belatacept (50% of early conversion). All these patients were without prophylaxis, and the mortality reached 33.3% [15]. This study also proposed to consider as a risk factor of opportunistic infection the estimated glomerular filtration rate (eGFR) at the time of belatacept conversion: the higher the eGFR, the lower the risk of infection. Even if PJP was documented under belatacept treatment, this treatment alone cannot be fully responsible for the infection of the patient. Indeed a few months after being converted from tacrolimus to belatacept, MMF was replaced by everolimus. It has been reported that everolimus-based therapy can induce interstitial lung diseases (ILD). In a retrospective series of 500 kidney-transplanted patients, Solazzo et al. [16] found 26 ILDs; of these, 12 cases (46.2%) were from infections (42.8% by P. jirovecii), whereas in 14 cases (53.8%) this was related to drug-induced ILD. Finally, there were other facilitating factors such as overimmunosuppression, chronic T-cell lymphopenia, and previous episode of treated acute rejection.
Even though the risk of opportunistic infections resides mostly within the first year post-transplant, the second year after transplantation seems to be still a high-risk period for developing PJP [2]. However, the actual duration of PJP prophylaxis varies between 6 and 12 months post-transplantation; because of this risk within the second year, the duration of prophylaxis should be reevaluated. Goto et al. [17] proposed long-term PJP prophylaxis using TMP-SMX, based on the three outbreaks of PJP they reported in patients who had stopped PJP prophylaxis after 3 months of treatment.
Before considering long-term prophylaxis of PJP using TMP-SMX, it would be helpful to have more data on renal toxicity after long-term exposure to TMP-SMX. Another option could be to conduct studies on reintroduction of PJP prophylaxis after a switch from calcineurin inhibitor-based to belatacept-based therapy. In particular, prophylaxis using a treatment that would not cause renal toxicity, such as monthly aerosol of pentamidine, could be assessed further. Currently, a compromise could be to continue regular biological evaluations in the second year after renal allograft transplantation regarding immunosuppression: lymphocytes, CD4+ T-cell counts, and IgG levels, even if the transplant was ABO and HLA compatible.
Statement of Ethics
Written informed consent for publication (including figures) was obtained from the patient, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Q. Perrier contributed to acquisition of data and writing of the manuscript. R. Tetaz and L. Rostaing provided supervision and mentorship. All the authors approved the final manuscript.
Fig. 1 Bilateral chest X-ray with alveolo-interstitial opacities.
Fig. 2 Evolution of biological markers linked to the management of Pneumocystis jirovecii pneumonia. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33708795 | 19,019,328 | 2021 |
What was the dosage of drug 'LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN'? | A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection.
Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that often develops in immunocompromised kidney-allograft recipients [1]. Several risks factors have been described: age, cytomegalovirus (CMV)-positive viremia, neutropenia, a lymphocyte count of <750/mm3 for more than 1 month (although a CD4+ T-cell of <200/µL is not a good biomarker in non-HIV patient), low plasma total gamma globulins, an acute-rejection episode, and immunosuppression treatment [2].
Renal toxicity was previously well described with high dose of trimethoprim-sulfamethoxazole (TMP-SMX) used in PJP treatment, i.e. acute tubular necrosis. SMX acts as a nephrotoxic agent through tubular precipitation and local production of crystal. Renal impermeant was also reported whatever the dose used, i.e. acute interstitial nephritis with immunologically induced hypersensitivity [3, 4]. Therefore, several studies have assessed the use of atovaquone or pentamidine to prevent PJP [5, 6]. Although the results are promising, TMP-SMX is still the first-choice prophylaxis [7]. In fact, the use of TMP-SMX as a prophylactic drug for PJP for 6–12 months after kidney transplantation can significantly decrease its incidence [8].
Herein, this case report describes the management and prevention of PJP in a kidney-allograft recipient receiving maintenance immunosuppressive therapy of belatacept, everolimus, plus corticosteroids.
Case Report
A 49-year-old HLA-sensitized male had end-stage renal disease that was secondary to autosomal dominant polycystic kidney disease, which had first been diagnosed when he was aged 30 years. In 2012, he received peritoneal dialysis for 1 year, and then hemodialysis for 2 years. He then received a kidney transplant in 2015 from a deceased donor. The donor and recipient were both CMV seronegative. The initial induction therapy was based on antithymocyte globulins (Thymoglobulin®, 0.5 mg/kg/day for 5 days) plus a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Serum-creatinine level at 1 month post-transplantation was 194 µmol/L.
At 3 months post-transplantation, serum creatinine had increased to 325 µmol/L, and the histology showed acute cellular rejection, which was treated with 3 boluses of methylprednisolone (10 mg/kg each). Despite the disappearance of inflammatory infiltrates within the interstitium (as seen in a follow-up allograft biopsy), renal function remained altered (creatinine at 319 µmol/L). In January 2017, the patient was converted to a belatacept-based calcineurin-free regimen, which led to recovery of renal function in 18 months: serum-creatinine level became 212 µmol/L. In August 2018, MMF was switched to the antiproliferative drug everolimus because of the risk of developing squamous-cell carcinoma. In December 2018, the patient developed a dry cough with a purulent sputum, although the fever resolved after 7 days of receiving amoxicillin. However, a few days later, he developed progressive and severe dyspnea, which led to his hospitalization 2 weeks later. In a clinical examination, the patient had tachypnea (32 breaths/min), and oxygen saturation was only at 88% in room air. Chest computed tomography showed diffuse bilateral alveolo-interstitial opacities suggesting an opportunistic infection (Fig. 1). The initial blood investigations revealed the following: C-reactive protein, 58 mg/L; low lymphocyte count (0.4 g/L) with no CD4 +T cells detected for 2 years; and hypogammaglobulinemia, i.e. immunoglobulin G (IgG) was 3.2 g/L compared to 4.2 g/L 5 months previously. Legionella, Aspergillus, and Pneumococcusantigenemias, Chlamydia, and Mycoplasma serologies, and a CMV DNAemia were all negative. Samples from a bronchoscopy and a bronchoalveolar lavage were negative for bacterial and viral pathogens (cultures and PCR testing) but revealed a high load of P. jirovecii DNA.
Because of respiratory gravity (i.e., PO2 = 60 mm Hg), the patient was given continuous oxygen support, intravenous corticosteroids (a single dose of 1 mg/kg of methylprednisone, which was then decreased to 0.5 mg/kg), and TMP-SMX (800/160 mg adjusted according to renal function).
After receiving these therapies for 7 days, the patient was weaned off oxygen, and his biological inflammatory markers were improved; however, there was 20% degradation in renal function (shown in Fig. 2). Because of the improved respiratory status but also the renal impairment we converted TMP-SMX to atovaquone for 21 days. The patient could then return home after 9 days of hospitalization with stable renal allograft function (creatinine: 227 µmol/L). Follow-up investigations showed normalization of CRP level, and renal allograft function returned to baseline values (creatinine: 200 µmol/L), and improvements were seen on radiological images. PJP prophylaxis for the next 6 months was pentamidine given as an aerosol monthly in the hospital. Belatacept (5 mg/kg every 4 weeks) was never stopped.
Discussion/Conclusion
At 3 years after renal ABO- and HLA-compatible allograft, and 2 years after conversion from tacrolimus to belatacept, our patient had developed acute PJP. He had presented several risks factors: immunosuppressive treatment (belatacept and everolimus), history of acute cellular rejection at 3 months post-transplantation, biological evidence of overimmunosuppression, i.e. low lymphocyte count with no CD4 T cell and decrease in IgG at 3.2 g/L. Indeed, antithymocyte globulins result in long-term lymphopenia. Crepin et al. [9] have reported that ATG delays thymic-dependent T cell reconstitution, increases the frequency of late-stage differentiated T cells, and promotes peripheral Treg expansion. Moreover, ATG is associated with persistent low values of T-cell relative telomere length and telomerase activity. Taken together, these data suggest that ATG induces accelerated immune senescence.
Hughes et al. [10] compared treating acute PJP with atovaquone or TMP-SMX. Patients treated with atovaquone “more often had no response” and had a higher mortality rate (7 vs. 0.6%, p = 0.003). Thus, TMP-SMX was the first treatment recommended to treat acute PJP [7]. At admission, our patient presented with acute-phase PJP with gravity criteria (he needed oxygen: PO2 = 60 mm Hg): at that time, the benefit-risk balance favored an aggressive induction treatment. Nevertheless, after 1 week, the benefit-risk balance became reversed in favor of preserving renal function according to respiratory improvement status. Thus, our patient was switched to receive atovaquone instead. After the induction treatment, he received pentamidine as the prophylaxis.
Belatacept, a new costimulation blocker has attracted interest as a treatment to preserve renal function, and improved cardiovascular/metabolic risk profile without infectious alarm signal confirmed by Vicenti and al. [11] after 7 years of use. Specific studies about early [12] or late [13] conversion to belatacept did not report PJP. The first case of lethal PCP under belatacept was described by Haidinger et al. [14] 4 years after transplantation in a multi-infected patient. Then, three other cases of PCP under belatacept were reported in ABO-incompatible transplantation [1]. A recent study showed that 34/280 patients had presented opportunistic infection after conversion to belatacept, 28.6% represented PJP, i.e. 10 patients about 10 months after conversion to belatacept (50% of early conversion). All these patients were without prophylaxis, and the mortality reached 33.3% [15]. This study also proposed to consider as a risk factor of opportunistic infection the estimated glomerular filtration rate (eGFR) at the time of belatacept conversion: the higher the eGFR, the lower the risk of infection. Even if PJP was documented under belatacept treatment, this treatment alone cannot be fully responsible for the infection of the patient. Indeed a few months after being converted from tacrolimus to belatacept, MMF was replaced by everolimus. It has been reported that everolimus-based therapy can induce interstitial lung diseases (ILD). In a retrospective series of 500 kidney-transplanted patients, Solazzo et al. [16] found 26 ILDs; of these, 12 cases (46.2%) were from infections (42.8% by P. jirovecii), whereas in 14 cases (53.8%) this was related to drug-induced ILD. Finally, there were other facilitating factors such as overimmunosuppression, chronic T-cell lymphopenia, and previous episode of treated acute rejection.
Even though the risk of opportunistic infections resides mostly within the first year post-transplant, the second year after transplantation seems to be still a high-risk period for developing PJP [2]. However, the actual duration of PJP prophylaxis varies between 6 and 12 months post-transplantation; because of this risk within the second year, the duration of prophylaxis should be reevaluated. Goto et al. [17] proposed long-term PJP prophylaxis using TMP-SMX, based on the three outbreaks of PJP they reported in patients who had stopped PJP prophylaxis after 3 months of treatment.
Before considering long-term prophylaxis of PJP using TMP-SMX, it would be helpful to have more data on renal toxicity after long-term exposure to TMP-SMX. Another option could be to conduct studies on reintroduction of PJP prophylaxis after a switch from calcineurin inhibitor-based to belatacept-based therapy. In particular, prophylaxis using a treatment that would not cause renal toxicity, such as monthly aerosol of pentamidine, could be assessed further. Currently, a compromise could be to continue regular biological evaluations in the second year after renal allograft transplantation regarding immunosuppression: lymphocytes, CD4+ T-cell counts, and IgG levels, even if the transplant was ABO and HLA compatible.
Statement of Ethics
Written informed consent for publication (including figures) was obtained from the patient, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Q. Perrier contributed to acquisition of data and writing of the manuscript. R. Tetaz and L. Rostaing provided supervision and mentorship. All the authors approved the final manuscript.
Fig. 1 Bilateral chest X-ray with alveolo-interstitial opacities.
Fig. 2 Evolution of biological markers linked to the management of Pneumocystis jirovecii pneumonia. | .5 MG/KG DAILY; 0.5 MG/KG/DAY FOR 5 DAYS | DrugDosageText | CC BY-NC | 33708795 | 18,975,559 | 2021 |
What was the dosage of drug 'SULFAMETHOXAZOLE\TRIMETHOPRIM'? | A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection.
Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that often develops in immunocompromised kidney-allograft recipients [1]. Several risks factors have been described: age, cytomegalovirus (CMV)-positive viremia, neutropenia, a lymphocyte count of <750/mm3 for more than 1 month (although a CD4+ T-cell of <200/µL is not a good biomarker in non-HIV patient), low plasma total gamma globulins, an acute-rejection episode, and immunosuppression treatment [2].
Renal toxicity was previously well described with high dose of trimethoprim-sulfamethoxazole (TMP-SMX) used in PJP treatment, i.e. acute tubular necrosis. SMX acts as a nephrotoxic agent through tubular precipitation and local production of crystal. Renal impermeant was also reported whatever the dose used, i.e. acute interstitial nephritis with immunologically induced hypersensitivity [3, 4]. Therefore, several studies have assessed the use of atovaquone or pentamidine to prevent PJP [5, 6]. Although the results are promising, TMP-SMX is still the first-choice prophylaxis [7]. In fact, the use of TMP-SMX as a prophylactic drug for PJP for 6–12 months after kidney transplantation can significantly decrease its incidence [8].
Herein, this case report describes the management and prevention of PJP in a kidney-allograft recipient receiving maintenance immunosuppressive therapy of belatacept, everolimus, plus corticosteroids.
Case Report
A 49-year-old HLA-sensitized male had end-stage renal disease that was secondary to autosomal dominant polycystic kidney disease, which had first been diagnosed when he was aged 30 years. In 2012, he received peritoneal dialysis for 1 year, and then hemodialysis for 2 years. He then received a kidney transplant in 2015 from a deceased donor. The donor and recipient were both CMV seronegative. The initial induction therapy was based on antithymocyte globulins (Thymoglobulin®, 0.5 mg/kg/day for 5 days) plus a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Serum-creatinine level at 1 month post-transplantation was 194 µmol/L.
At 3 months post-transplantation, serum creatinine had increased to 325 µmol/L, and the histology showed acute cellular rejection, which was treated with 3 boluses of methylprednisolone (10 mg/kg each). Despite the disappearance of inflammatory infiltrates within the interstitium (as seen in a follow-up allograft biopsy), renal function remained altered (creatinine at 319 µmol/L). In January 2017, the patient was converted to a belatacept-based calcineurin-free regimen, which led to recovery of renal function in 18 months: serum-creatinine level became 212 µmol/L. In August 2018, MMF was switched to the antiproliferative drug everolimus because of the risk of developing squamous-cell carcinoma. In December 2018, the patient developed a dry cough with a purulent sputum, although the fever resolved after 7 days of receiving amoxicillin. However, a few days later, he developed progressive and severe dyspnea, which led to his hospitalization 2 weeks later. In a clinical examination, the patient had tachypnea (32 breaths/min), and oxygen saturation was only at 88% in room air. Chest computed tomography showed diffuse bilateral alveolo-interstitial opacities suggesting an opportunistic infection (Fig. 1). The initial blood investigations revealed the following: C-reactive protein, 58 mg/L; low lymphocyte count (0.4 g/L) with no CD4 +T cells detected for 2 years; and hypogammaglobulinemia, i.e. immunoglobulin G (IgG) was 3.2 g/L compared to 4.2 g/L 5 months previously. Legionella, Aspergillus, and Pneumococcusantigenemias, Chlamydia, and Mycoplasma serologies, and a CMV DNAemia were all negative. Samples from a bronchoscopy and a bronchoalveolar lavage were negative for bacterial and viral pathogens (cultures and PCR testing) but revealed a high load of P. jirovecii DNA.
Because of respiratory gravity (i.e., PO2 = 60 mm Hg), the patient was given continuous oxygen support, intravenous corticosteroids (a single dose of 1 mg/kg of methylprednisone, which was then decreased to 0.5 mg/kg), and TMP-SMX (800/160 mg adjusted according to renal function).
After receiving these therapies for 7 days, the patient was weaned off oxygen, and his biological inflammatory markers were improved; however, there was 20% degradation in renal function (shown in Fig. 2). Because of the improved respiratory status but also the renal impairment we converted TMP-SMX to atovaquone for 21 days. The patient could then return home after 9 days of hospitalization with stable renal allograft function (creatinine: 227 µmol/L). Follow-up investigations showed normalization of CRP level, and renal allograft function returned to baseline values (creatinine: 200 µmol/L), and improvements were seen on radiological images. PJP prophylaxis for the next 6 months was pentamidine given as an aerosol monthly in the hospital. Belatacept (5 mg/kg every 4 weeks) was never stopped.
Discussion/Conclusion
At 3 years after renal ABO- and HLA-compatible allograft, and 2 years after conversion from tacrolimus to belatacept, our patient had developed acute PJP. He had presented several risks factors: immunosuppressive treatment (belatacept and everolimus), history of acute cellular rejection at 3 months post-transplantation, biological evidence of overimmunosuppression, i.e. low lymphocyte count with no CD4 T cell and decrease in IgG at 3.2 g/L. Indeed, antithymocyte globulins result in long-term lymphopenia. Crepin et al. [9] have reported that ATG delays thymic-dependent T cell reconstitution, increases the frequency of late-stage differentiated T cells, and promotes peripheral Treg expansion. Moreover, ATG is associated with persistent low values of T-cell relative telomere length and telomerase activity. Taken together, these data suggest that ATG induces accelerated immune senescence.
Hughes et al. [10] compared treating acute PJP with atovaquone or TMP-SMX. Patients treated with atovaquone “more often had no response” and had a higher mortality rate (7 vs. 0.6%, p = 0.003). Thus, TMP-SMX was the first treatment recommended to treat acute PJP [7]. At admission, our patient presented with acute-phase PJP with gravity criteria (he needed oxygen: PO2 = 60 mm Hg): at that time, the benefit-risk balance favored an aggressive induction treatment. Nevertheless, after 1 week, the benefit-risk balance became reversed in favor of preserving renal function according to respiratory improvement status. Thus, our patient was switched to receive atovaquone instead. After the induction treatment, he received pentamidine as the prophylaxis.
Belatacept, a new costimulation blocker has attracted interest as a treatment to preserve renal function, and improved cardiovascular/metabolic risk profile without infectious alarm signal confirmed by Vicenti and al. [11] after 7 years of use. Specific studies about early [12] or late [13] conversion to belatacept did not report PJP. The first case of lethal PCP under belatacept was described by Haidinger et al. [14] 4 years after transplantation in a multi-infected patient. Then, three other cases of PCP under belatacept were reported in ABO-incompatible transplantation [1]. A recent study showed that 34/280 patients had presented opportunistic infection after conversion to belatacept, 28.6% represented PJP, i.e. 10 patients about 10 months after conversion to belatacept (50% of early conversion). All these patients were without prophylaxis, and the mortality reached 33.3% [15]. This study also proposed to consider as a risk factor of opportunistic infection the estimated glomerular filtration rate (eGFR) at the time of belatacept conversion: the higher the eGFR, the lower the risk of infection. Even if PJP was documented under belatacept treatment, this treatment alone cannot be fully responsible for the infection of the patient. Indeed a few months after being converted from tacrolimus to belatacept, MMF was replaced by everolimus. It has been reported that everolimus-based therapy can induce interstitial lung diseases (ILD). In a retrospective series of 500 kidney-transplanted patients, Solazzo et al. [16] found 26 ILDs; of these, 12 cases (46.2%) were from infections (42.8% by P. jirovecii), whereas in 14 cases (53.8%) this was related to drug-induced ILD. Finally, there were other facilitating factors such as overimmunosuppression, chronic T-cell lymphopenia, and previous episode of treated acute rejection.
Even though the risk of opportunistic infections resides mostly within the first year post-transplant, the second year after transplantation seems to be still a high-risk period for developing PJP [2]. However, the actual duration of PJP prophylaxis varies between 6 and 12 months post-transplantation; because of this risk within the second year, the duration of prophylaxis should be reevaluated. Goto et al. [17] proposed long-term PJP prophylaxis using TMP-SMX, based on the three outbreaks of PJP they reported in patients who had stopped PJP prophylaxis after 3 months of treatment.
Before considering long-term prophylaxis of PJP using TMP-SMX, it would be helpful to have more data on renal toxicity after long-term exposure to TMP-SMX. Another option could be to conduct studies on reintroduction of PJP prophylaxis after a switch from calcineurin inhibitor-based to belatacept-based therapy. In particular, prophylaxis using a treatment that would not cause renal toxicity, such as monthly aerosol of pentamidine, could be assessed further. Currently, a compromise could be to continue regular biological evaluations in the second year after renal allograft transplantation regarding immunosuppression: lymphocytes, CD4+ T-cell counts, and IgG levels, even if the transplant was ABO and HLA compatible.
Statement of Ethics
Written informed consent for publication (including figures) was obtained from the patient, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Q. Perrier contributed to acquisition of data and writing of the manuscript. R. Tetaz and L. Rostaing provided supervision and mentorship. All the authors approved the final manuscript.
Fig. 1 Bilateral chest X-ray with alveolo-interstitial opacities.
Fig. 2 Evolution of biological markers linked to the management of Pneumocystis jirovecii pneumonia. | 800/160MG | DrugDosageText | CC BY-NC | 33708795 | 18,975,559 | 2021 |
What was the outcome of reaction 'Lymphopenia'? | A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection.
Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that often develops in immunocompromised kidney-allograft recipients [1]. Several risks factors have been described: age, cytomegalovirus (CMV)-positive viremia, neutropenia, a lymphocyte count of <750/mm3 for more than 1 month (although a CD4+ T-cell of <200/µL is not a good biomarker in non-HIV patient), low plasma total gamma globulins, an acute-rejection episode, and immunosuppression treatment [2].
Renal toxicity was previously well described with high dose of trimethoprim-sulfamethoxazole (TMP-SMX) used in PJP treatment, i.e. acute tubular necrosis. SMX acts as a nephrotoxic agent through tubular precipitation and local production of crystal. Renal impermeant was also reported whatever the dose used, i.e. acute interstitial nephritis with immunologically induced hypersensitivity [3, 4]. Therefore, several studies have assessed the use of atovaquone or pentamidine to prevent PJP [5, 6]. Although the results are promising, TMP-SMX is still the first-choice prophylaxis [7]. In fact, the use of TMP-SMX as a prophylactic drug for PJP for 6–12 months after kidney transplantation can significantly decrease its incidence [8].
Herein, this case report describes the management and prevention of PJP in a kidney-allograft recipient receiving maintenance immunosuppressive therapy of belatacept, everolimus, plus corticosteroids.
Case Report
A 49-year-old HLA-sensitized male had end-stage renal disease that was secondary to autosomal dominant polycystic kidney disease, which had first been diagnosed when he was aged 30 years. In 2012, he received peritoneal dialysis for 1 year, and then hemodialysis for 2 years. He then received a kidney transplant in 2015 from a deceased donor. The donor and recipient were both CMV seronegative. The initial induction therapy was based on antithymocyte globulins (Thymoglobulin®, 0.5 mg/kg/day for 5 days) plus a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Serum-creatinine level at 1 month post-transplantation was 194 µmol/L.
At 3 months post-transplantation, serum creatinine had increased to 325 µmol/L, and the histology showed acute cellular rejection, which was treated with 3 boluses of methylprednisolone (10 mg/kg each). Despite the disappearance of inflammatory infiltrates within the interstitium (as seen in a follow-up allograft biopsy), renal function remained altered (creatinine at 319 µmol/L). In January 2017, the patient was converted to a belatacept-based calcineurin-free regimen, which led to recovery of renal function in 18 months: serum-creatinine level became 212 µmol/L. In August 2018, MMF was switched to the antiproliferative drug everolimus because of the risk of developing squamous-cell carcinoma. In December 2018, the patient developed a dry cough with a purulent sputum, although the fever resolved after 7 days of receiving amoxicillin. However, a few days later, he developed progressive and severe dyspnea, which led to his hospitalization 2 weeks later. In a clinical examination, the patient had tachypnea (32 breaths/min), and oxygen saturation was only at 88% in room air. Chest computed tomography showed diffuse bilateral alveolo-interstitial opacities suggesting an opportunistic infection (Fig. 1). The initial blood investigations revealed the following: C-reactive protein, 58 mg/L; low lymphocyte count (0.4 g/L) with no CD4 +T cells detected for 2 years; and hypogammaglobulinemia, i.e. immunoglobulin G (IgG) was 3.2 g/L compared to 4.2 g/L 5 months previously. Legionella, Aspergillus, and Pneumococcusantigenemias, Chlamydia, and Mycoplasma serologies, and a CMV DNAemia were all negative. Samples from a bronchoscopy and a bronchoalveolar lavage were negative for bacterial and viral pathogens (cultures and PCR testing) but revealed a high load of P. jirovecii DNA.
Because of respiratory gravity (i.e., PO2 = 60 mm Hg), the patient was given continuous oxygen support, intravenous corticosteroids (a single dose of 1 mg/kg of methylprednisone, which was then decreased to 0.5 mg/kg), and TMP-SMX (800/160 mg adjusted according to renal function).
After receiving these therapies for 7 days, the patient was weaned off oxygen, and his biological inflammatory markers were improved; however, there was 20% degradation in renal function (shown in Fig. 2). Because of the improved respiratory status but also the renal impairment we converted TMP-SMX to atovaquone for 21 days. The patient could then return home after 9 days of hospitalization with stable renal allograft function (creatinine: 227 µmol/L). Follow-up investigations showed normalization of CRP level, and renal allograft function returned to baseline values (creatinine: 200 µmol/L), and improvements were seen on radiological images. PJP prophylaxis for the next 6 months was pentamidine given as an aerosol monthly in the hospital. Belatacept (5 mg/kg every 4 weeks) was never stopped.
Discussion/Conclusion
At 3 years after renal ABO- and HLA-compatible allograft, and 2 years after conversion from tacrolimus to belatacept, our patient had developed acute PJP. He had presented several risks factors: immunosuppressive treatment (belatacept and everolimus), history of acute cellular rejection at 3 months post-transplantation, biological evidence of overimmunosuppression, i.e. low lymphocyte count with no CD4 T cell and decrease in IgG at 3.2 g/L. Indeed, antithymocyte globulins result in long-term lymphopenia. Crepin et al. [9] have reported that ATG delays thymic-dependent T cell reconstitution, increases the frequency of late-stage differentiated T cells, and promotes peripheral Treg expansion. Moreover, ATG is associated with persistent low values of T-cell relative telomere length and telomerase activity. Taken together, these data suggest that ATG induces accelerated immune senescence.
Hughes et al. [10] compared treating acute PJP with atovaquone or TMP-SMX. Patients treated with atovaquone “more often had no response” and had a higher mortality rate (7 vs. 0.6%, p = 0.003). Thus, TMP-SMX was the first treatment recommended to treat acute PJP [7]. At admission, our patient presented with acute-phase PJP with gravity criteria (he needed oxygen: PO2 = 60 mm Hg): at that time, the benefit-risk balance favored an aggressive induction treatment. Nevertheless, after 1 week, the benefit-risk balance became reversed in favor of preserving renal function according to respiratory improvement status. Thus, our patient was switched to receive atovaquone instead. After the induction treatment, he received pentamidine as the prophylaxis.
Belatacept, a new costimulation blocker has attracted interest as a treatment to preserve renal function, and improved cardiovascular/metabolic risk profile without infectious alarm signal confirmed by Vicenti and al. [11] after 7 years of use. Specific studies about early [12] or late [13] conversion to belatacept did not report PJP. The first case of lethal PCP under belatacept was described by Haidinger et al. [14] 4 years after transplantation in a multi-infected patient. Then, three other cases of PCP under belatacept were reported in ABO-incompatible transplantation [1]. A recent study showed that 34/280 patients had presented opportunistic infection after conversion to belatacept, 28.6% represented PJP, i.e. 10 patients about 10 months after conversion to belatacept (50% of early conversion). All these patients were without prophylaxis, and the mortality reached 33.3% [15]. This study also proposed to consider as a risk factor of opportunistic infection the estimated glomerular filtration rate (eGFR) at the time of belatacept conversion: the higher the eGFR, the lower the risk of infection. Even if PJP was documented under belatacept treatment, this treatment alone cannot be fully responsible for the infection of the patient. Indeed a few months after being converted from tacrolimus to belatacept, MMF was replaced by everolimus. It has been reported that everolimus-based therapy can induce interstitial lung diseases (ILD). In a retrospective series of 500 kidney-transplanted patients, Solazzo et al. [16] found 26 ILDs; of these, 12 cases (46.2%) were from infections (42.8% by P. jirovecii), whereas in 14 cases (53.8%) this was related to drug-induced ILD. Finally, there were other facilitating factors such as overimmunosuppression, chronic T-cell lymphopenia, and previous episode of treated acute rejection.
Even though the risk of opportunistic infections resides mostly within the first year post-transplant, the second year after transplantation seems to be still a high-risk period for developing PJP [2]. However, the actual duration of PJP prophylaxis varies between 6 and 12 months post-transplantation; because of this risk within the second year, the duration of prophylaxis should be reevaluated. Goto et al. [17] proposed long-term PJP prophylaxis using TMP-SMX, based on the three outbreaks of PJP they reported in patients who had stopped PJP prophylaxis after 3 months of treatment.
Before considering long-term prophylaxis of PJP using TMP-SMX, it would be helpful to have more data on renal toxicity after long-term exposure to TMP-SMX. Another option could be to conduct studies on reintroduction of PJP prophylaxis after a switch from calcineurin inhibitor-based to belatacept-based therapy. In particular, prophylaxis using a treatment that would not cause renal toxicity, such as monthly aerosol of pentamidine, could be assessed further. Currently, a compromise could be to continue regular biological evaluations in the second year after renal allograft transplantation regarding immunosuppression: lymphocytes, CD4+ T-cell counts, and IgG levels, even if the transplant was ABO and HLA compatible.
Statement of Ethics
Written informed consent for publication (including figures) was obtained from the patient, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Q. Perrier contributed to acquisition of data and writing of the manuscript. R. Tetaz and L. Rostaing provided supervision and mentorship. All the authors approved the final manuscript.
Fig. 1 Bilateral chest X-ray with alveolo-interstitial opacities.
Fig. 2 Evolution of biological markers linked to the management of Pneumocystis jirovecii pneumonia. | Recovered | ReactionOutcome | CC BY-NC | 33708795 | 18,975,559 | 2021 |
What was the outcome of reaction 'No adverse event'? | A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection.
Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that often develops in immunocompromised kidney-allograft recipients [1]. Several risks factors have been described: age, cytomegalovirus (CMV)-positive viremia, neutropenia, a lymphocyte count of <750/mm3 for more than 1 month (although a CD4+ T-cell of <200/µL is not a good biomarker in non-HIV patient), low plasma total gamma globulins, an acute-rejection episode, and immunosuppression treatment [2].
Renal toxicity was previously well described with high dose of trimethoprim-sulfamethoxazole (TMP-SMX) used in PJP treatment, i.e. acute tubular necrosis. SMX acts as a nephrotoxic agent through tubular precipitation and local production of crystal. Renal impermeant was also reported whatever the dose used, i.e. acute interstitial nephritis with immunologically induced hypersensitivity [3, 4]. Therefore, several studies have assessed the use of atovaquone or pentamidine to prevent PJP [5, 6]. Although the results are promising, TMP-SMX is still the first-choice prophylaxis [7]. In fact, the use of TMP-SMX as a prophylactic drug for PJP for 6–12 months after kidney transplantation can significantly decrease its incidence [8].
Herein, this case report describes the management and prevention of PJP in a kidney-allograft recipient receiving maintenance immunosuppressive therapy of belatacept, everolimus, plus corticosteroids.
Case Report
A 49-year-old HLA-sensitized male had end-stage renal disease that was secondary to autosomal dominant polycystic kidney disease, which had first been diagnosed when he was aged 30 years. In 2012, he received peritoneal dialysis for 1 year, and then hemodialysis for 2 years. He then received a kidney transplant in 2015 from a deceased donor. The donor and recipient were both CMV seronegative. The initial induction therapy was based on antithymocyte globulins (Thymoglobulin®, 0.5 mg/kg/day for 5 days) plus a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Serum-creatinine level at 1 month post-transplantation was 194 µmol/L.
At 3 months post-transplantation, serum creatinine had increased to 325 µmol/L, and the histology showed acute cellular rejection, which was treated with 3 boluses of methylprednisolone (10 mg/kg each). Despite the disappearance of inflammatory infiltrates within the interstitium (as seen in a follow-up allograft biopsy), renal function remained altered (creatinine at 319 µmol/L). In January 2017, the patient was converted to a belatacept-based calcineurin-free regimen, which led to recovery of renal function in 18 months: serum-creatinine level became 212 µmol/L. In August 2018, MMF was switched to the antiproliferative drug everolimus because of the risk of developing squamous-cell carcinoma. In December 2018, the patient developed a dry cough with a purulent sputum, although the fever resolved after 7 days of receiving amoxicillin. However, a few days later, he developed progressive and severe dyspnea, which led to his hospitalization 2 weeks later. In a clinical examination, the patient had tachypnea (32 breaths/min), and oxygen saturation was only at 88% in room air. Chest computed tomography showed diffuse bilateral alveolo-interstitial opacities suggesting an opportunistic infection (Fig. 1). The initial blood investigations revealed the following: C-reactive protein, 58 mg/L; low lymphocyte count (0.4 g/L) with no CD4 +T cells detected for 2 years; and hypogammaglobulinemia, i.e. immunoglobulin G (IgG) was 3.2 g/L compared to 4.2 g/L 5 months previously. Legionella, Aspergillus, and Pneumococcusantigenemias, Chlamydia, and Mycoplasma serologies, and a CMV DNAemia were all negative. Samples from a bronchoscopy and a bronchoalveolar lavage were negative for bacterial and viral pathogens (cultures and PCR testing) but revealed a high load of P. jirovecii DNA.
Because of respiratory gravity (i.e., PO2 = 60 mm Hg), the patient was given continuous oxygen support, intravenous corticosteroids (a single dose of 1 mg/kg of methylprednisone, which was then decreased to 0.5 mg/kg), and TMP-SMX (800/160 mg adjusted according to renal function).
After receiving these therapies for 7 days, the patient was weaned off oxygen, and his biological inflammatory markers were improved; however, there was 20% degradation in renal function (shown in Fig. 2). Because of the improved respiratory status but also the renal impairment we converted TMP-SMX to atovaquone for 21 days. The patient could then return home after 9 days of hospitalization with stable renal allograft function (creatinine: 227 µmol/L). Follow-up investigations showed normalization of CRP level, and renal allograft function returned to baseline values (creatinine: 200 µmol/L), and improvements were seen on radiological images. PJP prophylaxis for the next 6 months was pentamidine given as an aerosol monthly in the hospital. Belatacept (5 mg/kg every 4 weeks) was never stopped.
Discussion/Conclusion
At 3 years after renal ABO- and HLA-compatible allograft, and 2 years after conversion from tacrolimus to belatacept, our patient had developed acute PJP. He had presented several risks factors: immunosuppressive treatment (belatacept and everolimus), history of acute cellular rejection at 3 months post-transplantation, biological evidence of overimmunosuppression, i.e. low lymphocyte count with no CD4 T cell and decrease in IgG at 3.2 g/L. Indeed, antithymocyte globulins result in long-term lymphopenia. Crepin et al. [9] have reported that ATG delays thymic-dependent T cell reconstitution, increases the frequency of late-stage differentiated T cells, and promotes peripheral Treg expansion. Moreover, ATG is associated with persistent low values of T-cell relative telomere length and telomerase activity. Taken together, these data suggest that ATG induces accelerated immune senescence.
Hughes et al. [10] compared treating acute PJP with atovaquone or TMP-SMX. Patients treated with atovaquone “more often had no response” and had a higher mortality rate (7 vs. 0.6%, p = 0.003). Thus, TMP-SMX was the first treatment recommended to treat acute PJP [7]. At admission, our patient presented with acute-phase PJP with gravity criteria (he needed oxygen: PO2 = 60 mm Hg): at that time, the benefit-risk balance favored an aggressive induction treatment. Nevertheless, after 1 week, the benefit-risk balance became reversed in favor of preserving renal function according to respiratory improvement status. Thus, our patient was switched to receive atovaquone instead. After the induction treatment, he received pentamidine as the prophylaxis.
Belatacept, a new costimulation blocker has attracted interest as a treatment to preserve renal function, and improved cardiovascular/metabolic risk profile without infectious alarm signal confirmed by Vicenti and al. [11] after 7 years of use. Specific studies about early [12] or late [13] conversion to belatacept did not report PJP. The first case of lethal PCP under belatacept was described by Haidinger et al. [14] 4 years after transplantation in a multi-infected patient. Then, three other cases of PCP under belatacept were reported in ABO-incompatible transplantation [1]. A recent study showed that 34/280 patients had presented opportunistic infection after conversion to belatacept, 28.6% represented PJP, i.e. 10 patients about 10 months after conversion to belatacept (50% of early conversion). All these patients were without prophylaxis, and the mortality reached 33.3% [15]. This study also proposed to consider as a risk factor of opportunistic infection the estimated glomerular filtration rate (eGFR) at the time of belatacept conversion: the higher the eGFR, the lower the risk of infection. Even if PJP was documented under belatacept treatment, this treatment alone cannot be fully responsible for the infection of the patient. Indeed a few months after being converted from tacrolimus to belatacept, MMF was replaced by everolimus. It has been reported that everolimus-based therapy can induce interstitial lung diseases (ILD). In a retrospective series of 500 kidney-transplanted patients, Solazzo et al. [16] found 26 ILDs; of these, 12 cases (46.2%) were from infections (42.8% by P. jirovecii), whereas in 14 cases (53.8%) this was related to drug-induced ILD. Finally, there were other facilitating factors such as overimmunosuppression, chronic T-cell lymphopenia, and previous episode of treated acute rejection.
Even though the risk of opportunistic infections resides mostly within the first year post-transplant, the second year after transplantation seems to be still a high-risk period for developing PJP [2]. However, the actual duration of PJP prophylaxis varies between 6 and 12 months post-transplantation; because of this risk within the second year, the duration of prophylaxis should be reevaluated. Goto et al. [17] proposed long-term PJP prophylaxis using TMP-SMX, based on the three outbreaks of PJP they reported in patients who had stopped PJP prophylaxis after 3 months of treatment.
Before considering long-term prophylaxis of PJP using TMP-SMX, it would be helpful to have more data on renal toxicity after long-term exposure to TMP-SMX. Another option could be to conduct studies on reintroduction of PJP prophylaxis after a switch from calcineurin inhibitor-based to belatacept-based therapy. In particular, prophylaxis using a treatment that would not cause renal toxicity, such as monthly aerosol of pentamidine, could be assessed further. Currently, a compromise could be to continue regular biological evaluations in the second year after renal allograft transplantation regarding immunosuppression: lymphocytes, CD4+ T-cell counts, and IgG levels, even if the transplant was ABO and HLA compatible.
Statement of Ethics
Written informed consent for publication (including figures) was obtained from the patient, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Q. Perrier contributed to acquisition of data and writing of the manuscript. R. Tetaz and L. Rostaing provided supervision and mentorship. All the authors approved the final manuscript.
Fig. 1 Bilateral chest X-ray with alveolo-interstitial opacities.
Fig. 2 Evolution of biological markers linked to the management of Pneumocystis jirovecii pneumonia. | Recovering | ReactionOutcome | CC BY-NC | 33708795 | 19,019,328 | 2021 |
What was the outcome of reaction 'Pneumocystis jirovecii pneumonia'? | A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection.
Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that often develops in immunocompromised kidney-allograft recipients [1]. Several risks factors have been described: age, cytomegalovirus (CMV)-positive viremia, neutropenia, a lymphocyte count of <750/mm3 for more than 1 month (although a CD4+ T-cell of <200/µL is not a good biomarker in non-HIV patient), low plasma total gamma globulins, an acute-rejection episode, and immunosuppression treatment [2].
Renal toxicity was previously well described with high dose of trimethoprim-sulfamethoxazole (TMP-SMX) used in PJP treatment, i.e. acute tubular necrosis. SMX acts as a nephrotoxic agent through tubular precipitation and local production of crystal. Renal impermeant was also reported whatever the dose used, i.e. acute interstitial nephritis with immunologically induced hypersensitivity [3, 4]. Therefore, several studies have assessed the use of atovaquone or pentamidine to prevent PJP [5, 6]. Although the results are promising, TMP-SMX is still the first-choice prophylaxis [7]. In fact, the use of TMP-SMX as a prophylactic drug for PJP for 6–12 months after kidney transplantation can significantly decrease its incidence [8].
Herein, this case report describes the management and prevention of PJP in a kidney-allograft recipient receiving maintenance immunosuppressive therapy of belatacept, everolimus, plus corticosteroids.
Case Report
A 49-year-old HLA-sensitized male had end-stage renal disease that was secondary to autosomal dominant polycystic kidney disease, which had first been diagnosed when he was aged 30 years. In 2012, he received peritoneal dialysis for 1 year, and then hemodialysis for 2 years. He then received a kidney transplant in 2015 from a deceased donor. The donor and recipient were both CMV seronegative. The initial induction therapy was based on antithymocyte globulins (Thymoglobulin®, 0.5 mg/kg/day for 5 days) plus a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Serum-creatinine level at 1 month post-transplantation was 194 µmol/L.
At 3 months post-transplantation, serum creatinine had increased to 325 µmol/L, and the histology showed acute cellular rejection, which was treated with 3 boluses of methylprednisolone (10 mg/kg each). Despite the disappearance of inflammatory infiltrates within the interstitium (as seen in a follow-up allograft biopsy), renal function remained altered (creatinine at 319 µmol/L). In January 2017, the patient was converted to a belatacept-based calcineurin-free regimen, which led to recovery of renal function in 18 months: serum-creatinine level became 212 µmol/L. In August 2018, MMF was switched to the antiproliferative drug everolimus because of the risk of developing squamous-cell carcinoma. In December 2018, the patient developed a dry cough with a purulent sputum, although the fever resolved after 7 days of receiving amoxicillin. However, a few days later, he developed progressive and severe dyspnea, which led to his hospitalization 2 weeks later. In a clinical examination, the patient had tachypnea (32 breaths/min), and oxygen saturation was only at 88% in room air. Chest computed tomography showed diffuse bilateral alveolo-interstitial opacities suggesting an opportunistic infection (Fig. 1). The initial blood investigations revealed the following: C-reactive protein, 58 mg/L; low lymphocyte count (0.4 g/L) with no CD4 +T cells detected for 2 years; and hypogammaglobulinemia, i.e. immunoglobulin G (IgG) was 3.2 g/L compared to 4.2 g/L 5 months previously. Legionella, Aspergillus, and Pneumococcusantigenemias, Chlamydia, and Mycoplasma serologies, and a CMV DNAemia were all negative. Samples from a bronchoscopy and a bronchoalveolar lavage were negative for bacterial and viral pathogens (cultures and PCR testing) but revealed a high load of P. jirovecii DNA.
Because of respiratory gravity (i.e., PO2 = 60 mm Hg), the patient was given continuous oxygen support, intravenous corticosteroids (a single dose of 1 mg/kg of methylprednisone, which was then decreased to 0.5 mg/kg), and TMP-SMX (800/160 mg adjusted according to renal function).
After receiving these therapies for 7 days, the patient was weaned off oxygen, and his biological inflammatory markers were improved; however, there was 20% degradation in renal function (shown in Fig. 2). Because of the improved respiratory status but also the renal impairment we converted TMP-SMX to atovaquone for 21 days. The patient could then return home after 9 days of hospitalization with stable renal allograft function (creatinine: 227 µmol/L). Follow-up investigations showed normalization of CRP level, and renal allograft function returned to baseline values (creatinine: 200 µmol/L), and improvements were seen on radiological images. PJP prophylaxis for the next 6 months was pentamidine given as an aerosol monthly in the hospital. Belatacept (5 mg/kg every 4 weeks) was never stopped.
Discussion/Conclusion
At 3 years after renal ABO- and HLA-compatible allograft, and 2 years after conversion from tacrolimus to belatacept, our patient had developed acute PJP. He had presented several risks factors: immunosuppressive treatment (belatacept and everolimus), history of acute cellular rejection at 3 months post-transplantation, biological evidence of overimmunosuppression, i.e. low lymphocyte count with no CD4 T cell and decrease in IgG at 3.2 g/L. Indeed, antithymocyte globulins result in long-term lymphopenia. Crepin et al. [9] have reported that ATG delays thymic-dependent T cell reconstitution, increases the frequency of late-stage differentiated T cells, and promotes peripheral Treg expansion. Moreover, ATG is associated with persistent low values of T-cell relative telomere length and telomerase activity. Taken together, these data suggest that ATG induces accelerated immune senescence.
Hughes et al. [10] compared treating acute PJP with atovaquone or TMP-SMX. Patients treated with atovaquone “more often had no response” and had a higher mortality rate (7 vs. 0.6%, p = 0.003). Thus, TMP-SMX was the first treatment recommended to treat acute PJP [7]. At admission, our patient presented with acute-phase PJP with gravity criteria (he needed oxygen: PO2 = 60 mm Hg): at that time, the benefit-risk balance favored an aggressive induction treatment. Nevertheless, after 1 week, the benefit-risk balance became reversed in favor of preserving renal function according to respiratory improvement status. Thus, our patient was switched to receive atovaquone instead. After the induction treatment, he received pentamidine as the prophylaxis.
Belatacept, a new costimulation blocker has attracted interest as a treatment to preserve renal function, and improved cardiovascular/metabolic risk profile without infectious alarm signal confirmed by Vicenti and al. [11] after 7 years of use. Specific studies about early [12] or late [13] conversion to belatacept did not report PJP. The first case of lethal PCP under belatacept was described by Haidinger et al. [14] 4 years after transplantation in a multi-infected patient. Then, three other cases of PCP under belatacept were reported in ABO-incompatible transplantation [1]. A recent study showed that 34/280 patients had presented opportunistic infection after conversion to belatacept, 28.6% represented PJP, i.e. 10 patients about 10 months after conversion to belatacept (50% of early conversion). All these patients were without prophylaxis, and the mortality reached 33.3% [15]. This study also proposed to consider as a risk factor of opportunistic infection the estimated glomerular filtration rate (eGFR) at the time of belatacept conversion: the higher the eGFR, the lower the risk of infection. Even if PJP was documented under belatacept treatment, this treatment alone cannot be fully responsible for the infection of the patient. Indeed a few months after being converted from tacrolimus to belatacept, MMF was replaced by everolimus. It has been reported that everolimus-based therapy can induce interstitial lung diseases (ILD). In a retrospective series of 500 kidney-transplanted patients, Solazzo et al. [16] found 26 ILDs; of these, 12 cases (46.2%) were from infections (42.8% by P. jirovecii), whereas in 14 cases (53.8%) this was related to drug-induced ILD. Finally, there were other facilitating factors such as overimmunosuppression, chronic T-cell lymphopenia, and previous episode of treated acute rejection.
Even though the risk of opportunistic infections resides mostly within the first year post-transplant, the second year after transplantation seems to be still a high-risk period for developing PJP [2]. However, the actual duration of PJP prophylaxis varies between 6 and 12 months post-transplantation; because of this risk within the second year, the duration of prophylaxis should be reevaluated. Goto et al. [17] proposed long-term PJP prophylaxis using TMP-SMX, based on the three outbreaks of PJP they reported in patients who had stopped PJP prophylaxis after 3 months of treatment.
Before considering long-term prophylaxis of PJP using TMP-SMX, it would be helpful to have more data on renal toxicity after long-term exposure to TMP-SMX. Another option could be to conduct studies on reintroduction of PJP prophylaxis after a switch from calcineurin inhibitor-based to belatacept-based therapy. In particular, prophylaxis using a treatment that would not cause renal toxicity, such as monthly aerosol of pentamidine, could be assessed further. Currently, a compromise could be to continue regular biological evaluations in the second year after renal allograft transplantation regarding immunosuppression: lymphocytes, CD4+ T-cell counts, and IgG levels, even if the transplant was ABO and HLA compatible.
Statement of Ethics
Written informed consent for publication (including figures) was obtained from the patient, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Q. Perrier contributed to acquisition of data and writing of the manuscript. R. Tetaz and L. Rostaing provided supervision and mentorship. All the authors approved the final manuscript.
Fig. 1 Bilateral chest X-ray with alveolo-interstitial opacities.
Fig. 2 Evolution of biological markers linked to the management of Pneumocystis jirovecii pneumonia. | Recovered | ReactionOutcome | CC BY-NC | 33708795 | 18,975,559 | 2021 |
What was the outcome of reaction 'Renal impairment'? | A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection.
Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that often develops in immunocompromised kidney-allograft recipients [1]. Several risks factors have been described: age, cytomegalovirus (CMV)-positive viremia, neutropenia, a lymphocyte count of <750/mm3 for more than 1 month (although a CD4+ T-cell of <200/µL is not a good biomarker in non-HIV patient), low plasma total gamma globulins, an acute-rejection episode, and immunosuppression treatment [2].
Renal toxicity was previously well described with high dose of trimethoprim-sulfamethoxazole (TMP-SMX) used in PJP treatment, i.e. acute tubular necrosis. SMX acts as a nephrotoxic agent through tubular precipitation and local production of crystal. Renal impermeant was also reported whatever the dose used, i.e. acute interstitial nephritis with immunologically induced hypersensitivity [3, 4]. Therefore, several studies have assessed the use of atovaquone or pentamidine to prevent PJP [5, 6]. Although the results are promising, TMP-SMX is still the first-choice prophylaxis [7]. In fact, the use of TMP-SMX as a prophylactic drug for PJP for 6–12 months after kidney transplantation can significantly decrease its incidence [8].
Herein, this case report describes the management and prevention of PJP in a kidney-allograft recipient receiving maintenance immunosuppressive therapy of belatacept, everolimus, plus corticosteroids.
Case Report
A 49-year-old HLA-sensitized male had end-stage renal disease that was secondary to autosomal dominant polycystic kidney disease, which had first been diagnosed when he was aged 30 years. In 2012, he received peritoneal dialysis for 1 year, and then hemodialysis for 2 years. He then received a kidney transplant in 2015 from a deceased donor. The donor and recipient were both CMV seronegative. The initial induction therapy was based on antithymocyte globulins (Thymoglobulin®, 0.5 mg/kg/day for 5 days) plus a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Serum-creatinine level at 1 month post-transplantation was 194 µmol/L.
At 3 months post-transplantation, serum creatinine had increased to 325 µmol/L, and the histology showed acute cellular rejection, which was treated with 3 boluses of methylprednisolone (10 mg/kg each). Despite the disappearance of inflammatory infiltrates within the interstitium (as seen in a follow-up allograft biopsy), renal function remained altered (creatinine at 319 µmol/L). In January 2017, the patient was converted to a belatacept-based calcineurin-free regimen, which led to recovery of renal function in 18 months: serum-creatinine level became 212 µmol/L. In August 2018, MMF was switched to the antiproliferative drug everolimus because of the risk of developing squamous-cell carcinoma. In December 2018, the patient developed a dry cough with a purulent sputum, although the fever resolved after 7 days of receiving amoxicillin. However, a few days later, he developed progressive and severe dyspnea, which led to his hospitalization 2 weeks later. In a clinical examination, the patient had tachypnea (32 breaths/min), and oxygen saturation was only at 88% in room air. Chest computed tomography showed diffuse bilateral alveolo-interstitial opacities suggesting an opportunistic infection (Fig. 1). The initial blood investigations revealed the following: C-reactive protein, 58 mg/L; low lymphocyte count (0.4 g/L) with no CD4 +T cells detected for 2 years; and hypogammaglobulinemia, i.e. immunoglobulin G (IgG) was 3.2 g/L compared to 4.2 g/L 5 months previously. Legionella, Aspergillus, and Pneumococcusantigenemias, Chlamydia, and Mycoplasma serologies, and a CMV DNAemia were all negative. Samples from a bronchoscopy and a bronchoalveolar lavage were negative for bacterial and viral pathogens (cultures and PCR testing) but revealed a high load of P. jirovecii DNA.
Because of respiratory gravity (i.e., PO2 = 60 mm Hg), the patient was given continuous oxygen support, intravenous corticosteroids (a single dose of 1 mg/kg of methylprednisone, which was then decreased to 0.5 mg/kg), and TMP-SMX (800/160 mg adjusted according to renal function).
After receiving these therapies for 7 days, the patient was weaned off oxygen, and his biological inflammatory markers were improved; however, there was 20% degradation in renal function (shown in Fig. 2). Because of the improved respiratory status but also the renal impairment we converted TMP-SMX to atovaquone for 21 days. The patient could then return home after 9 days of hospitalization with stable renal allograft function (creatinine: 227 µmol/L). Follow-up investigations showed normalization of CRP level, and renal allograft function returned to baseline values (creatinine: 200 µmol/L), and improvements were seen on radiological images. PJP prophylaxis for the next 6 months was pentamidine given as an aerosol monthly in the hospital. Belatacept (5 mg/kg every 4 weeks) was never stopped.
Discussion/Conclusion
At 3 years after renal ABO- and HLA-compatible allograft, and 2 years after conversion from tacrolimus to belatacept, our patient had developed acute PJP. He had presented several risks factors: immunosuppressive treatment (belatacept and everolimus), history of acute cellular rejection at 3 months post-transplantation, biological evidence of overimmunosuppression, i.e. low lymphocyte count with no CD4 T cell and decrease in IgG at 3.2 g/L. Indeed, antithymocyte globulins result in long-term lymphopenia. Crepin et al. [9] have reported that ATG delays thymic-dependent T cell reconstitution, increases the frequency of late-stage differentiated T cells, and promotes peripheral Treg expansion. Moreover, ATG is associated with persistent low values of T-cell relative telomere length and telomerase activity. Taken together, these data suggest that ATG induces accelerated immune senescence.
Hughes et al. [10] compared treating acute PJP with atovaquone or TMP-SMX. Patients treated with atovaquone “more often had no response” and had a higher mortality rate (7 vs. 0.6%, p = 0.003). Thus, TMP-SMX was the first treatment recommended to treat acute PJP [7]. At admission, our patient presented with acute-phase PJP with gravity criteria (he needed oxygen: PO2 = 60 mm Hg): at that time, the benefit-risk balance favored an aggressive induction treatment. Nevertheless, after 1 week, the benefit-risk balance became reversed in favor of preserving renal function according to respiratory improvement status. Thus, our patient was switched to receive atovaquone instead. After the induction treatment, he received pentamidine as the prophylaxis.
Belatacept, a new costimulation blocker has attracted interest as a treatment to preserve renal function, and improved cardiovascular/metabolic risk profile without infectious alarm signal confirmed by Vicenti and al. [11] after 7 years of use. Specific studies about early [12] or late [13] conversion to belatacept did not report PJP. The first case of lethal PCP under belatacept was described by Haidinger et al. [14] 4 years after transplantation in a multi-infected patient. Then, three other cases of PCP under belatacept were reported in ABO-incompatible transplantation [1]. A recent study showed that 34/280 patients had presented opportunistic infection after conversion to belatacept, 28.6% represented PJP, i.e. 10 patients about 10 months after conversion to belatacept (50% of early conversion). All these patients were without prophylaxis, and the mortality reached 33.3% [15]. This study also proposed to consider as a risk factor of opportunistic infection the estimated glomerular filtration rate (eGFR) at the time of belatacept conversion: the higher the eGFR, the lower the risk of infection. Even if PJP was documented under belatacept treatment, this treatment alone cannot be fully responsible for the infection of the patient. Indeed a few months after being converted from tacrolimus to belatacept, MMF was replaced by everolimus. It has been reported that everolimus-based therapy can induce interstitial lung diseases (ILD). In a retrospective series of 500 kidney-transplanted patients, Solazzo et al. [16] found 26 ILDs; of these, 12 cases (46.2%) were from infections (42.8% by P. jirovecii), whereas in 14 cases (53.8%) this was related to drug-induced ILD. Finally, there were other facilitating factors such as overimmunosuppression, chronic T-cell lymphopenia, and previous episode of treated acute rejection.
Even though the risk of opportunistic infections resides mostly within the first year post-transplant, the second year after transplantation seems to be still a high-risk period for developing PJP [2]. However, the actual duration of PJP prophylaxis varies between 6 and 12 months post-transplantation; because of this risk within the second year, the duration of prophylaxis should be reevaluated. Goto et al. [17] proposed long-term PJP prophylaxis using TMP-SMX, based on the three outbreaks of PJP they reported in patients who had stopped PJP prophylaxis after 3 months of treatment.
Before considering long-term prophylaxis of PJP using TMP-SMX, it would be helpful to have more data on renal toxicity after long-term exposure to TMP-SMX. Another option could be to conduct studies on reintroduction of PJP prophylaxis after a switch from calcineurin inhibitor-based to belatacept-based therapy. In particular, prophylaxis using a treatment that would not cause renal toxicity, such as monthly aerosol of pentamidine, could be assessed further. Currently, a compromise could be to continue regular biological evaluations in the second year after renal allograft transplantation regarding immunosuppression: lymphocytes, CD4+ T-cell counts, and IgG levels, even if the transplant was ABO and HLA compatible.
Statement of Ethics
Written informed consent for publication (including figures) was obtained from the patient, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Q. Perrier contributed to acquisition of data and writing of the manuscript. R. Tetaz and L. Rostaing provided supervision and mentorship. All the authors approved the final manuscript.
Fig. 1 Bilateral chest X-ray with alveolo-interstitial opacities.
Fig. 2 Evolution of biological markers linked to the management of Pneumocystis jirovecii pneumonia. | Recovered | ReactionOutcome | CC BY-NC | 33708795 | 19,071,017 | 2021 |
What was the outcome of reaction 'Transplant rejection'? | A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection.
Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Introduction
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection that often develops in immunocompromised kidney-allograft recipients [1]. Several risks factors have been described: age, cytomegalovirus (CMV)-positive viremia, neutropenia, a lymphocyte count of <750/mm3 for more than 1 month (although a CD4+ T-cell of <200/µL is not a good biomarker in non-HIV patient), low plasma total gamma globulins, an acute-rejection episode, and immunosuppression treatment [2].
Renal toxicity was previously well described with high dose of trimethoprim-sulfamethoxazole (TMP-SMX) used in PJP treatment, i.e. acute tubular necrosis. SMX acts as a nephrotoxic agent through tubular precipitation and local production of crystal. Renal impermeant was also reported whatever the dose used, i.e. acute interstitial nephritis with immunologically induced hypersensitivity [3, 4]. Therefore, several studies have assessed the use of atovaquone or pentamidine to prevent PJP [5, 6]. Although the results are promising, TMP-SMX is still the first-choice prophylaxis [7]. In fact, the use of TMP-SMX as a prophylactic drug for PJP for 6–12 months after kidney transplantation can significantly decrease its incidence [8].
Herein, this case report describes the management and prevention of PJP in a kidney-allograft recipient receiving maintenance immunosuppressive therapy of belatacept, everolimus, plus corticosteroids.
Case Report
A 49-year-old HLA-sensitized male had end-stage renal disease that was secondary to autosomal dominant polycystic kidney disease, which had first been diagnosed when he was aged 30 years. In 2012, he received peritoneal dialysis for 1 year, and then hemodialysis for 2 years. He then received a kidney transplant in 2015 from a deceased donor. The donor and recipient were both CMV seronegative. The initial induction therapy was based on antithymocyte globulins (Thymoglobulin®, 0.5 mg/kg/day for 5 days) plus a maintenance immunosuppressive regimen of tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Serum-creatinine level at 1 month post-transplantation was 194 µmol/L.
At 3 months post-transplantation, serum creatinine had increased to 325 µmol/L, and the histology showed acute cellular rejection, which was treated with 3 boluses of methylprednisolone (10 mg/kg each). Despite the disappearance of inflammatory infiltrates within the interstitium (as seen in a follow-up allograft biopsy), renal function remained altered (creatinine at 319 µmol/L). In January 2017, the patient was converted to a belatacept-based calcineurin-free regimen, which led to recovery of renal function in 18 months: serum-creatinine level became 212 µmol/L. In August 2018, MMF was switched to the antiproliferative drug everolimus because of the risk of developing squamous-cell carcinoma. In December 2018, the patient developed a dry cough with a purulent sputum, although the fever resolved after 7 days of receiving amoxicillin. However, a few days later, he developed progressive and severe dyspnea, which led to his hospitalization 2 weeks later. In a clinical examination, the patient had tachypnea (32 breaths/min), and oxygen saturation was only at 88% in room air. Chest computed tomography showed diffuse bilateral alveolo-interstitial opacities suggesting an opportunistic infection (Fig. 1). The initial blood investigations revealed the following: C-reactive protein, 58 mg/L; low lymphocyte count (0.4 g/L) with no CD4 +T cells detected for 2 years; and hypogammaglobulinemia, i.e. immunoglobulin G (IgG) was 3.2 g/L compared to 4.2 g/L 5 months previously. Legionella, Aspergillus, and Pneumococcusantigenemias, Chlamydia, and Mycoplasma serologies, and a CMV DNAemia were all negative. Samples from a bronchoscopy and a bronchoalveolar lavage were negative for bacterial and viral pathogens (cultures and PCR testing) but revealed a high load of P. jirovecii DNA.
Because of respiratory gravity (i.e., PO2 = 60 mm Hg), the patient was given continuous oxygen support, intravenous corticosteroids (a single dose of 1 mg/kg of methylprednisone, which was then decreased to 0.5 mg/kg), and TMP-SMX (800/160 mg adjusted according to renal function).
After receiving these therapies for 7 days, the patient was weaned off oxygen, and his biological inflammatory markers were improved; however, there was 20% degradation in renal function (shown in Fig. 2). Because of the improved respiratory status but also the renal impairment we converted TMP-SMX to atovaquone for 21 days. The patient could then return home after 9 days of hospitalization with stable renal allograft function (creatinine: 227 µmol/L). Follow-up investigations showed normalization of CRP level, and renal allograft function returned to baseline values (creatinine: 200 µmol/L), and improvements were seen on radiological images. PJP prophylaxis for the next 6 months was pentamidine given as an aerosol monthly in the hospital. Belatacept (5 mg/kg every 4 weeks) was never stopped.
Discussion/Conclusion
At 3 years after renal ABO- and HLA-compatible allograft, and 2 years after conversion from tacrolimus to belatacept, our patient had developed acute PJP. He had presented several risks factors: immunosuppressive treatment (belatacept and everolimus), history of acute cellular rejection at 3 months post-transplantation, biological evidence of overimmunosuppression, i.e. low lymphocyte count with no CD4 T cell and decrease in IgG at 3.2 g/L. Indeed, antithymocyte globulins result in long-term lymphopenia. Crepin et al. [9] have reported that ATG delays thymic-dependent T cell reconstitution, increases the frequency of late-stage differentiated T cells, and promotes peripheral Treg expansion. Moreover, ATG is associated with persistent low values of T-cell relative telomere length and telomerase activity. Taken together, these data suggest that ATG induces accelerated immune senescence.
Hughes et al. [10] compared treating acute PJP with atovaquone or TMP-SMX. Patients treated with atovaquone “more often had no response” and had a higher mortality rate (7 vs. 0.6%, p = 0.003). Thus, TMP-SMX was the first treatment recommended to treat acute PJP [7]. At admission, our patient presented with acute-phase PJP with gravity criteria (he needed oxygen: PO2 = 60 mm Hg): at that time, the benefit-risk balance favored an aggressive induction treatment. Nevertheless, after 1 week, the benefit-risk balance became reversed in favor of preserving renal function according to respiratory improvement status. Thus, our patient was switched to receive atovaquone instead. After the induction treatment, he received pentamidine as the prophylaxis.
Belatacept, a new costimulation blocker has attracted interest as a treatment to preserve renal function, and improved cardiovascular/metabolic risk profile without infectious alarm signal confirmed by Vicenti and al. [11] after 7 years of use. Specific studies about early [12] or late [13] conversion to belatacept did not report PJP. The first case of lethal PCP under belatacept was described by Haidinger et al. [14] 4 years after transplantation in a multi-infected patient. Then, three other cases of PCP under belatacept were reported in ABO-incompatible transplantation [1]. A recent study showed that 34/280 patients had presented opportunistic infection after conversion to belatacept, 28.6% represented PJP, i.e. 10 patients about 10 months after conversion to belatacept (50% of early conversion). All these patients were without prophylaxis, and the mortality reached 33.3% [15]. This study also proposed to consider as a risk factor of opportunistic infection the estimated glomerular filtration rate (eGFR) at the time of belatacept conversion: the higher the eGFR, the lower the risk of infection. Even if PJP was documented under belatacept treatment, this treatment alone cannot be fully responsible for the infection of the patient. Indeed a few months after being converted from tacrolimus to belatacept, MMF was replaced by everolimus. It has been reported that everolimus-based therapy can induce interstitial lung diseases (ILD). In a retrospective series of 500 kidney-transplanted patients, Solazzo et al. [16] found 26 ILDs; of these, 12 cases (46.2%) were from infections (42.8% by P. jirovecii), whereas in 14 cases (53.8%) this was related to drug-induced ILD. Finally, there were other facilitating factors such as overimmunosuppression, chronic T-cell lymphopenia, and previous episode of treated acute rejection.
Even though the risk of opportunistic infections resides mostly within the first year post-transplant, the second year after transplantation seems to be still a high-risk period for developing PJP [2]. However, the actual duration of PJP prophylaxis varies between 6 and 12 months post-transplantation; because of this risk within the second year, the duration of prophylaxis should be reevaluated. Goto et al. [17] proposed long-term PJP prophylaxis using TMP-SMX, based on the three outbreaks of PJP they reported in patients who had stopped PJP prophylaxis after 3 months of treatment.
Before considering long-term prophylaxis of PJP using TMP-SMX, it would be helpful to have more data on renal toxicity after long-term exposure to TMP-SMX. Another option could be to conduct studies on reintroduction of PJP prophylaxis after a switch from calcineurin inhibitor-based to belatacept-based therapy. In particular, prophylaxis using a treatment that would not cause renal toxicity, such as monthly aerosol of pentamidine, could be assessed further. Currently, a compromise could be to continue regular biological evaluations in the second year after renal allograft transplantation regarding immunosuppression: lymphocytes, CD4+ T-cell counts, and IgG levels, even if the transplant was ABO and HLA compatible.
Statement of Ethics
Written informed consent for publication (including figures) was obtained from the patient, and the research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Q. Perrier contributed to acquisition of data and writing of the manuscript. R. Tetaz and L. Rostaing provided supervision and mentorship. All the authors approved the final manuscript.
Fig. 1 Bilateral chest X-ray with alveolo-interstitial opacities.
Fig. 2 Evolution of biological markers linked to the management of Pneumocystis jirovecii pneumonia. | Recovered | ReactionOutcome | CC BY-NC | 33708795 | 19,071,017 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arterial disorder'. | Low-Vacuum Scanning Electron Microscopy to Assess Histopathological Resolution of Class V Lupus Nephritis: A Case Report.
Lupus nephritis (LN) is most frequently associated with poor outcomes in patients with systemic lupus erythematosus (SLE). LN manifests as histopathological changes in the kidney caused by immune complex formation and deposition. In particular, immunoglobulin G (IgG) deposits are frequently observed by immunofluorescence staining, which helps to establish the diagnosis of LN. In this case report, we describe a 57-year-old woman with SLE who had been undergoing treatment on an outpatient basis for 11 years. Her first and second renal biopsies revealed class V LN with a coarsely granular pattern of IgG deposition in the peripheral capillary walls. However, her third renal biopsy showed no IgG deposition, which indicated histopathological resolution of her class V LN. We used low-vacuum scanning electron microscopy (LV-SEM) to examine the three-dimensional structural alterations in her glomerular basement membranes. In this report, we describe findings that indicated resorption of epithelial deposits, that is, resolution of LN. The results of repeated kidney biopsies confirmed by LV-SEM suggested the possibility of a state unrelated to LN.
Introduction
Systemic lupus erythematosus (SLE) is a multiorgan, systemic autoimmune disease with clinical and serological heterogeneity [1]. Lupus nephritis (LN) is one of the most common and devastating manifestations of SLE. In approximately 50% of affected patients, SLE results in LN [2]. Although the overall mortality of patients with SLE has decreased remarkably in recent decades, renal disease remains the leading cause of death in these patients [3]. LN has histopathological diversity and is explained by immune complex deposition [4, 5]. Renal biopsy allows for evaluation of LN activity and determination of therapy based on histological features. Although individual patterns of immunofluorescence (IF) staining are highly variable, some general characteristics are applicable to all classes [4]. In more than 90% of patients with SLE, IF staining of the peripheral capillary wall or mesangial areas is seen microscopically. In particular, immunoglobulin G (IgG) deposits are observed using IF staining in almost every patient with LN [4, 6]. In most cases of LN, immune complexes in blood plasma are deposited on glomeruli, which can be seen using light microscopy (LM), IF, and transmission electron microscopy (TEM) [7].
In the present case, we performed three renal biopsies in 9 years. The first and second renal biopsies revealed IgG deposits in the peripheral capillary walls; however, the third renal biopsy showed no IgG deposits. Conventional renal biopsy paraffin sections stained with periodic acid methenamine silver (PAM) can be directly observed using low-vacuum scanning electron microscopy (LV-SEM). In conventional electron microscopy, only a small area can be viewed; however, LV-SEM enables scanning over broad areas of the specimen and in three dimensions under high magnification [8, 9]. We considered that evaluation using LV-SEM might be useful for the histopathological assessment of renal glomerular basement membrane (GBM) alterations. We therefore evaluated the two sides of the GBM using LV-SEM and examined the washout phenomenon of the membranous form of LN. We herein highlight the histopathological findings of this case.
Case Presentation
Clinical Information
A 57-year-old woman had presented with Raynaud's phenomenon and fever of unknown etiology at the age of 48 years. Laboratory analysis showed positive anti-nuclear autoantibody and renal insufficiency with proteinuria (1.33 g/g Cr). The titer of anti-double-stranded DNA autoantibody was slightly elevated (3.1 IU/mL). She was diagnosed with SLE in accordance with the Systemic Lupus International Collaborating Clinics criteria [10]. The patient's first renal biopsy was undertaken at this time. Examination of the biopsy specimen led to a diagnosis of class V LN in accordance with the World Health Organization classification [9]. According to this diagnosis, she was treated with oral prednisolone, and tacrolimus was added at the age of 49 years. These treatments were successful, and the urine protein level decreased remarkably 4 years after treatment was started (to around 0.3–0.4 g/g Cr). At the age of 53 years, she was treated with dose-reduced tacrolimus because the effectiveness of these treatments had been confirmed. Despite the slow improvement in her renal function, the severity of her proteinuria gradually increased during the 4 years since the first biopsy. We suspected recurrence, and she therefore underwent a second biopsy at the age of 54 years. This repeat biopsy also revealed class V LN. Based on these findings, mycophenolate mofetil at 1,250 mg/day was added to the treatment regimen.
At the age of 57 years, laboratory studies revealed low SLE activity with a normal complete blood count, normal complement protein levels, and an anti-double-stranded DNA antibody titer of 5.8 IU/mL; however, proteinuria was present (>2 g/g Cr) (Table 1). Therefore, she underwent a third renal biopsy at the age of 57 years. At this time, the patient's clinical course and immunological investigation indicated no progression of SLE. Because the pathological findings indicated negative conversion of IgG, we considered that the activity of LN had been lost. These pathological results could explain the decreased SLE activity, and the class V LN was presumed to have resolved.
The patient was subsequently treated with antihypertensive drugs with a focus on angiotensin II receptor antagonists. Following treatment, her proteinuria decreased to 0.5 g/g Cr.
Renal Biopsies
The patient's first renal biopsy was performed at the age of 48 years. Histopathological examination using LM revealed several foamy formations and a generalized diffuse thickening of the GBM, which manifested as prominent spikes on PAM silver staining (Fig. 1a1). On IF staining, coarsely granular deposits of IgG, C3, and C1q were evident in the capillary walls (Fig. 1a2). TEM revealed abundant subepithelial deposits lining all capillary loops (Fig. 1a3). The patient was diagnosed with LN class V according to the International Society of Nephrology/Renal Pathology Society classification.
The second biopsy at the age of 54 years revealed reduced spike formation and a bubbly appearance (stippling) under LM examination (Fig. 1b1). IF staining showed similar findings; coarsely granular deposits of IgG, C3, and C1q were evident in the capillary basement membrane (Fig. 1b2). On TEM, smaller electron-dense deposits than in the first renal biopsy suggested a resorptive process (Fig. 1b3). A well-developed GBM reaction surrounded the deposits with overlying foot process effacement. These findings also indicated type V LN.
The third biopsy at the age of 57 years revealed advanced glomerulosclerosis (5/25 glomeruli), and PAM silver staining exhibited a primarily bubbly appearance and dome patterns; the spikes had almost disappeared on LM examination (Fig. 1c1). Conversely, the IF findings showed a scattered distribution of the IgG deposits with negative C3 and C1q (Fig. 1c2). TEM also revealed a marked decrease in the electron density of the deposits that had been clearly seen in the previous two biopsies. Instead, GBM thickening and wrinkling were seen (Fig. 1c3). We doubted that the results of TEM and IF therefore differed from those of LM. Another remarkable finding on LM was arteriolar hyalinosis, which could be explained as arteriolopathy caused by calcineurin inhibitors. No evidence of calcineurin inhibitor toxicity such as striped interstitial fibrosis or tubular atrophy was observed. Tubular and interstitial lesions were attributed to the effect of renal sclerosis because of hypertension. The increase in urinary protein excretion could be explained by severe arterial sclerosis and calcineurin inhibitor-induced arteriolopathy rather than exacerbation of LN.
C4d is described as a byproduct of activation of the classical and lectin pathways. Because C4d acts as a positive marker for an immune complex-mediated mechanism in glomerular nephritis, C4d staining can be helpful in revealing immune complex deposition [11]. Unfortunately, we could not examine the C4d properties of the deposits using frozen sections because of a lack of additional tissue remaining in the block. Therefore, to confirm that LN was not the main cause of the clinical proteinuria, we investigated the GBM using a different method.
For further evaluation, we observed the GBM in all three biopsy specimens using LV-SEM (Hitachi Tabletop microscope TM4000; Hitachi High-Technologies Corp., Tokyo, Japan). In the first renal biopsy at the age of 48 years, LV-SEM of glomeruli retrieved from formalin-fixed paraffin-embedded tissue (PAM stain) revealed extensive and numerous subepithelial holes where deposits were thought to have been present. Additionally, well-developed GBM material formed spikes around the holes (Fig. 2a1). However, these holes were not found on the glomerular capillary luminal side (Fig. 2a2). This finding corresponded to Ehrenreich-Churg stage II membranous nephropathy (MN). The second renal biopsy at the age of 54 years showed a well-developed GBM reaction surrounding the holes where deposits might have been present; this finding was equivalent to Ehrenreich-Churg stage III MN (Fig. 2b1). Epithelium had formed and covered holes found in the first renal biopsy tissue, and it was difficult to see holes when looking down from the subepithelial side (Fig. 2b1). The GBM of the glomerular capillary lumina was almost covered by basement membrane material, and holes were still only partially open (Fig. 2b2). The third renal biopsy at the age of 57 years exhibited epithelium covered by newly formed GBM material, with openings in the GBM inward toward the glomerular capillary lumen (Fig. 2c1, c2). We speculated that the holes in the glomerular capillary luminal side might emerge when immune complex deposits in the GBM wash out.
In studying the third renal biopsy specimen, we also drew a comparison between the IF findings of the scattered distribution of the deposits and the LV-SEM findings. We stained frozen sections for IF with PAM and examined them with LV-SEM. We compared and observed the same glomeruli (Fig. 3). No IgG staining was confirmed using IF, which suggested that no deposits were present in the GBM (Fig. 3a). However, many cavities were confirmed using LV-SEM (FIG. 3b). Therefore, it was considered that no deposit was present in the many holes, and it was presumed that washout of the immune complex deposits occurred in the membranous LN. Overall, further observation of the GBM with LV-SEM confirmed resolution of class V LN. This case was similar to stage IV MN according to the Ehrenreich-Churg staging criteria.
A case report by Nonaka et al. [12] described the conventional TEM assessment of subepithelial deposits in a patient with mild membranous LN. However, few cases of LN evaluated using LV-SEM in which the loss of immune complex deposits was discovered have been reported. Clinicians emphasize IgG deposition in the diagnosis of LN. Many clinicians tend to consider that LN is highly unlikely if IgG is negative using IF examination. In the present case, however, the diagnosis of LN was confirmed in the first and second renal biopsies.
This is our first experience of a case in which the pathological findings were presumed to indicate a state of resolution of class V LN, and we thought that this was a highly contradictory finding. We had doubts regarding whether the histopathological findings of LN disappear (as in common MN) as the disease activity of SLE decreases.
Discussion/Conclusion
In the present study, we found that membranous LN diminished or resolved over the course of the three renal biopsies. To help clarify this process, we evaluated the patient's kidney biopsy tissue using LV-SEM, which allows for observation of both sides of the GBM. By studying the three-dimensional structure of the GBM using LV-SEM, we confirmed the formation of holes on the glomerular capillary luminal side. From these findings, we suspected that the same pathology of the membrane washout phenomenon that occurs in MN occurred in our patient with LN.
LV-SEM sometimes outperforms the conventional technique, TEM. TEM is the superior technique for investigating cross-sectional images of various components in glomeruli; however, performing three-dimensional and whole/wide observations using ultrathin sections is difficult because of the limitation of the observable size. LV-SEM can be used to evaluate the three-dimensional ultrastructural changes of the glomerular extracellular matrices in the same specimen used for LM. It thus provides more detailed three-dimensional information [8, 9]. Therefore, to review the morphological alterations of the glomeruli in a three-dimensional, broad area, we examined the LM slides of the renal biopsy specimens using LV-SEM.
LV-SEM examination of the first biopsy revealed many openings or holes in the subepithelium, consistent with the LM, IF, and TEM findings. The second renal biopsy showed a well-developed GBM reaction surrounding the openings or holes with overlying foot process effacement. These LV-SEM results were almost identical to those of TEM. The third renal biopsy showed openings on the thickened GBM inward toward the glomerular capillary lumina and loss of the electron density of the deposits in TEM. We confirmed the findings of some openings or holes in the GBM on the luminal side of the vessel using LV-SEM. Thus, we suspected that the deposits were washed out through these holes. In other words, the findings we confirmed using LV-SEM might result from washout of the immune complexes (only the cavity remained after washout). This concept allows for the possibility of finding IgG positivity on IF, which can be said to be an essential marker of LN. IgG was negative using IF in the tissue from the third renal biopsy in this patient.
Furthermore, it is possible that LV-SEM might be useful for monitoring disease, in contrast to interpreting potentially challenging serological results. An example is M-type phospholipase A2 receptor (PLA2R)-negative MN. PLA2R-negative secondary MN is generally characterized by the irregular distribution and size of subepithelial deposits and the presence of irregular subendothelial and mesangial deposits in glomeruli. We believe that there may be some difference in the GBM of PRA2R-positive or -negative MN evaluated in detail using LV-SEM.
The Ehrenreich-Churg classification divides MN into four pathological stages according to the state of immune complex deposition and change in the GBM [13]. Stage IV MN is characterized by loss of the electron density of the deposits, transition to a “washout” state, and development of electron-lucent zones within an irregularly thickened GBM [13]. Furthermore, the GBM recovers to an almost normal morphology in stage V MN [14]. The GBM returns to its normal form without deposition or thickening in the state of washed-out MN. In the present case, however, LM did not show findings consistent with normalization of the GBM morphology, similar to the washout image seen in stage IV or V MN, and changes such as thickening and spike formation persisted. However, IgG and C3 deposits cannot be seen using IF staining. TEM also exhibited few deposits. This series of pathophysiological findings has been confirmed by observations on resolving glomerulopathy in serial allograft biopsies [15].
Based on these results, we postulated a pathological process beginning with LN that caused deposition of immune complexes on the GBM. A decrease in LN activity then led to loss of these deposits as the disease progressed to a state of stage V MN washout, which results in a bubbly appearance. That is, despite resolution of LN, LM showed a remarkable change in the GBM. When LM shows noticeable changes in the GBM and specific clinical findings are present (excessive urinary protein), clinicians will usually think that the cause is LN.
The opening on the GBM is normally covered by vascular endothelium. However, in MN, complement complexes might injure the GBM by inducing the production of reactive oxygen species, thus altering the membrane structure [16]. At that time, a large proportion of the immune complex might have passed through the GBM from the glomerular capillary luminal side toward the epithelial side and nephrosis developed. We suspected that in the present case, this backward event (from the epithelial side toward the glomerular capillary luminal side) could have occurred during the LN washout phase. In other words, we suspected the possibility that these holes observed on the glomerular capillary luminal side were formed when the immune complexes were washed out.
In conclusion, our patient exhibited a loss of LN activity and a change to a state of resolution of class V LN. Renal biopsy revealed negative conversion of IgG on IF, and spikes and domes were present in the GBM on LM. We believe that the evaluation of three-dimensional structural alterations in GBM using LV-SEM might be a useful approach for assessing variation in renal biopsies over time.
Statement of Ethics
This study was conducted according to the guidelines laid down in the World Medical Association Declaration of Helsinki. Informed consent was obtained from the patient described in this case report, and the consent allowed their data to be stored, as required by the Hiroshima University Hospital. Written consent to publish this information was obtained from the patient (images and publication).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not funded by any third party.
Author Contributions
M.Y., S.H., and T.D. contributed to the data collection. S.H. and T.M. designed the research. Y.M. and A.S. evaluated the pathological tissue. M.Y. and S.H. performed the primary manuscript preparation. M.Y., S.H., T.D., and T.M. wrote the paper. T.M. has primary responsibility for the final content. M.Y., S.H., T.D., Y.M., and A.S. reviewed the paper and revised it critically. All authors read and approved the final manuscript.
Acknowledgments
We thank Angela Morben, DVM, ELS, and Andrea Baird, MD, from Edanz Group (https://en-author-services.edanzgroup.com/), for editing drafts of the manuscript.
Fig. 1 Renal biopsy findings. a First renal biopsy. a1 LM revealed that the basement membrane was thickened and exhibited mainly spikes (red arrowheads) (PAM stain). Scale bar, 25 μm. a2 IF staining demonstrated coarsely granular deposits of IgG, C3, and C1q in the capillary walls (IF microscopy, IgG, C3, C1q; ×200). a3 TEM showed abundant subepithelial deposits. The pattern was equivalent to Ehrenreich-Churg stage II MN. Scale bar, 2 µm (TEM). b Second renal biopsy. b1 The basement membrane showed a global increase in thickening and a bubbly appearance on LM (red arrowheads). This appearance was comparable with Ehrenreich-Churg stage III MN (PAM stain). Scale bar, 50 μm. b2 IF exhibited coarsely granular deposits of IgG, C3, and C1q in the capillary basement membrane, as in the previous examination (IF microscopy, IgG, C3, C1q; ×200). b3 TEM examination showed that the dense deposits were smaller and had been partly resorbed. A well-developed basement membrane reaction surrounded the deposits with overlying foot process effacement. Scale bar, 2 µm (TEM). c Third renal biopsy. c1 The basement membrane was thickened and exhibited a general meandering-like wrinkling pattern as seen on LM. The bubbly appearance was the same as in the second biopsies (PAM stain). Scale bar, 50 μm. c2 IF showed almost negative conversion of IgG and negative C3 and C1q (IF microscopy, IgG, C3, C1q; ×200). c3 On TEM, the basement membrane showed global thickening, wrinkling, and podocyte foot process effacement. The electron density of the deposits was unclear. Scale bar, 2 µm (TEM). C, complement; IF, immunofluorescence; IgG, immunoglobulin G; LM, light microscopy; MN, membranous nephropathy; PAM, periodic acid methenamine silver; TEM, transmission electron microscopy.
Fig. 2 Renal biopsy findings using LV-SEM. a First renal biopsy. a1 An image from the epithelial side of the GBM. Basement membrane material accumulated between many holes (deposit-like appearance) and projected into the urinary space as “spikes” (red arrowheads). The holes were not covered with basement membrane. Scale bar, 2.5 μm. a2 An image from the glomerular capillary lumina. The GBM of the glomerular capillary luminal side was covered by the material of the basement membrane, and no opening was seen (blue arrowheads). Scale bar, 2.5 μm. b Second renal biopsy. b1 An image from the epithelial side of the GBM. Intramembranous holes were observed. These holes (deposit-like appearance) were surrounded by well-developed basement membrane material (red arrowheads). In the subepithelium of the GBM, basement membrane material was newly formed on the holes, and the holes seen in a1 could not be confirmed from the epithelium side view. Scale bar, 5 μm. b2 An image from the glomerular capillary lumina. The GBM of the glomerular capillary lumina was almost covered by basement membrane material, and holes were still only partially open. Scale bar, 2.5 μm. c Third renal biopsy. c1 An image from the epithelial side of the GBM. Thickening of the basement membrane was still present. Vacuolation was present in potential spaces where the deposits might have been. The holes on the epithelium side shown in a1 were hardly observed. Scale bar, 2.5 μm. c2 An image from the glomerular capillary lumina. In contrast to c1, openings were present on the glomerular basement membrane inward toward the glomerular capillary lumina (blue arrowheads). Electron-lucent-like areas probably represented resorption of prior subepithelial immune complexes. Scale bar, 5 μm. GBM, glomerular basement membrane; LV-SEM, low-vacuum scanning electron microscopy.
Fig. 3 Comparison between IF microscopy and LV-SEM findings. a PAM stain of an IF-stained specimen. IF staining seemed to be almost nonexistent (red arrowhead and circle). b LV-SEM findings did not clearly confirm the immune complex deposition in the area (red arrowhead and circle). Examination of the site with LV-SEM indicated washout of the immune complex deposition. IF, immunofluorescence; LV-SEM, low-vacuum scanning electron microscopy; PAM, periodic acid methenamine silver.
Table 1 Patient's laboratory results upon admission at the age of 57 years
Parameter Value Reference range
Urine
pH 5.5 5.0–6.5
Red blood cells, /HPF 0–1 <5
Fatty casts, /WF 1–4 Negative
Epithelial casts, /WF 1–4 Negative
Urine protein/creatinine ratio, g/g 2.68 <0.15
N-acetyl-β-D-glucosaminidase, IU/L 13.2 0.7–11.2
β2-Microglobulin, µg/L 0.75 <230
Blood
Leukocyte count, /µL 4,750 4,500–9,000
Lymphocytes, /µL 940 1,200–3,690
Hemoglobin, g/dL 11.9 13.6–17.0
Platelet count, ×104/µL 20.7 14–36
Urea nitrogen, mg/dL 21.4 8.0–22.0
Creatinine, mg/dL 0.85 0.60–1.10
Estimated GFR, mL/min/1.73 m2 53 >90
Uric acid, mg/dL 6.0 3.6–7.0
Total protein, g/dL 6.2 6.7–8.3
Albumin, g/dL 3.7 4.0–5.0
Sodium, mEq/L 140 138–146
Potassium, mEq/L 5.3 3.6–4.9
Chloride, mEq/L 108 99–109
Corrected serum calcium, mg/dL 8.8 8.6–10.4
Phosphate, mg/dL 3.5 2.5–4.7
C-reactive protein, mg/dL 0.07 <0.30
CH50, CH50/mL 48.7 25–48
C3, mg/dL 98 65–135
C4, mg/dL 26 13–35
IgG, mg/dL 630 870–1,700
IgA, mg/dL 170 110–410
IgM, mg/dL 18 33–190
Anti-nuclear antibody ×320 <×40
(staining patterns) homologous, speckled
Anti-ssDNA antibody, IU/mL 2.8 <2.0
Anti-dsDNA antibody, IU/mL 5.8 <2.0
CH50, 50% hemolytic complement; dsDNA, double-stranded DNA; GFR, glomerular filtration rate; HPF, high-power field; Ig, immunoglobulin; ssDNA, single-stranded DNA; WF, whole field. | PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33708798 | 19,404,881 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arteriosclerosis'. | Low-Vacuum Scanning Electron Microscopy to Assess Histopathological Resolution of Class V Lupus Nephritis: A Case Report.
Lupus nephritis (LN) is most frequently associated with poor outcomes in patients with systemic lupus erythematosus (SLE). LN manifests as histopathological changes in the kidney caused by immune complex formation and deposition. In particular, immunoglobulin G (IgG) deposits are frequently observed by immunofluorescence staining, which helps to establish the diagnosis of LN. In this case report, we describe a 57-year-old woman with SLE who had been undergoing treatment on an outpatient basis for 11 years. Her first and second renal biopsies revealed class V LN with a coarsely granular pattern of IgG deposition in the peripheral capillary walls. However, her third renal biopsy showed no IgG deposition, which indicated histopathological resolution of her class V LN. We used low-vacuum scanning electron microscopy (LV-SEM) to examine the three-dimensional structural alterations in her glomerular basement membranes. In this report, we describe findings that indicated resorption of epithelial deposits, that is, resolution of LN. The results of repeated kidney biopsies confirmed by LV-SEM suggested the possibility of a state unrelated to LN.
Introduction
Systemic lupus erythematosus (SLE) is a multiorgan, systemic autoimmune disease with clinical and serological heterogeneity [1]. Lupus nephritis (LN) is one of the most common and devastating manifestations of SLE. In approximately 50% of affected patients, SLE results in LN [2]. Although the overall mortality of patients with SLE has decreased remarkably in recent decades, renal disease remains the leading cause of death in these patients [3]. LN has histopathological diversity and is explained by immune complex deposition [4, 5]. Renal biopsy allows for evaluation of LN activity and determination of therapy based on histological features. Although individual patterns of immunofluorescence (IF) staining are highly variable, some general characteristics are applicable to all classes [4]. In more than 90% of patients with SLE, IF staining of the peripheral capillary wall or mesangial areas is seen microscopically. In particular, immunoglobulin G (IgG) deposits are observed using IF staining in almost every patient with LN [4, 6]. In most cases of LN, immune complexes in blood plasma are deposited on glomeruli, which can be seen using light microscopy (LM), IF, and transmission electron microscopy (TEM) [7].
In the present case, we performed three renal biopsies in 9 years. The first and second renal biopsies revealed IgG deposits in the peripheral capillary walls; however, the third renal biopsy showed no IgG deposits. Conventional renal biopsy paraffin sections stained with periodic acid methenamine silver (PAM) can be directly observed using low-vacuum scanning electron microscopy (LV-SEM). In conventional electron microscopy, only a small area can be viewed; however, LV-SEM enables scanning over broad areas of the specimen and in three dimensions under high magnification [8, 9]. We considered that evaluation using LV-SEM might be useful for the histopathological assessment of renal glomerular basement membrane (GBM) alterations. We therefore evaluated the two sides of the GBM using LV-SEM and examined the washout phenomenon of the membranous form of LN. We herein highlight the histopathological findings of this case.
Case Presentation
Clinical Information
A 57-year-old woman had presented with Raynaud's phenomenon and fever of unknown etiology at the age of 48 years. Laboratory analysis showed positive anti-nuclear autoantibody and renal insufficiency with proteinuria (1.33 g/g Cr). The titer of anti-double-stranded DNA autoantibody was slightly elevated (3.1 IU/mL). She was diagnosed with SLE in accordance with the Systemic Lupus International Collaborating Clinics criteria [10]. The patient's first renal biopsy was undertaken at this time. Examination of the biopsy specimen led to a diagnosis of class V LN in accordance with the World Health Organization classification [9]. According to this diagnosis, she was treated with oral prednisolone, and tacrolimus was added at the age of 49 years. These treatments were successful, and the urine protein level decreased remarkably 4 years after treatment was started (to around 0.3–0.4 g/g Cr). At the age of 53 years, she was treated with dose-reduced tacrolimus because the effectiveness of these treatments had been confirmed. Despite the slow improvement in her renal function, the severity of her proteinuria gradually increased during the 4 years since the first biopsy. We suspected recurrence, and she therefore underwent a second biopsy at the age of 54 years. This repeat biopsy also revealed class V LN. Based on these findings, mycophenolate mofetil at 1,250 mg/day was added to the treatment regimen.
At the age of 57 years, laboratory studies revealed low SLE activity with a normal complete blood count, normal complement protein levels, and an anti-double-stranded DNA antibody titer of 5.8 IU/mL; however, proteinuria was present (>2 g/g Cr) (Table 1). Therefore, she underwent a third renal biopsy at the age of 57 years. At this time, the patient's clinical course and immunological investigation indicated no progression of SLE. Because the pathological findings indicated negative conversion of IgG, we considered that the activity of LN had been lost. These pathological results could explain the decreased SLE activity, and the class V LN was presumed to have resolved.
The patient was subsequently treated with antihypertensive drugs with a focus on angiotensin II receptor antagonists. Following treatment, her proteinuria decreased to 0.5 g/g Cr.
Renal Biopsies
The patient's first renal biopsy was performed at the age of 48 years. Histopathological examination using LM revealed several foamy formations and a generalized diffuse thickening of the GBM, which manifested as prominent spikes on PAM silver staining (Fig. 1a1). On IF staining, coarsely granular deposits of IgG, C3, and C1q were evident in the capillary walls (Fig. 1a2). TEM revealed abundant subepithelial deposits lining all capillary loops (Fig. 1a3). The patient was diagnosed with LN class V according to the International Society of Nephrology/Renal Pathology Society classification.
The second biopsy at the age of 54 years revealed reduced spike formation and a bubbly appearance (stippling) under LM examination (Fig. 1b1). IF staining showed similar findings; coarsely granular deposits of IgG, C3, and C1q were evident in the capillary basement membrane (Fig. 1b2). On TEM, smaller electron-dense deposits than in the first renal biopsy suggested a resorptive process (Fig. 1b3). A well-developed GBM reaction surrounded the deposits with overlying foot process effacement. These findings also indicated type V LN.
The third biopsy at the age of 57 years revealed advanced glomerulosclerosis (5/25 glomeruli), and PAM silver staining exhibited a primarily bubbly appearance and dome patterns; the spikes had almost disappeared on LM examination (Fig. 1c1). Conversely, the IF findings showed a scattered distribution of the IgG deposits with negative C3 and C1q (Fig. 1c2). TEM also revealed a marked decrease in the electron density of the deposits that had been clearly seen in the previous two biopsies. Instead, GBM thickening and wrinkling were seen (Fig. 1c3). We doubted that the results of TEM and IF therefore differed from those of LM. Another remarkable finding on LM was arteriolar hyalinosis, which could be explained as arteriolopathy caused by calcineurin inhibitors. No evidence of calcineurin inhibitor toxicity such as striped interstitial fibrosis or tubular atrophy was observed. Tubular and interstitial lesions were attributed to the effect of renal sclerosis because of hypertension. The increase in urinary protein excretion could be explained by severe arterial sclerosis and calcineurin inhibitor-induced arteriolopathy rather than exacerbation of LN.
C4d is described as a byproduct of activation of the classical and lectin pathways. Because C4d acts as a positive marker for an immune complex-mediated mechanism in glomerular nephritis, C4d staining can be helpful in revealing immune complex deposition [11]. Unfortunately, we could not examine the C4d properties of the deposits using frozen sections because of a lack of additional tissue remaining in the block. Therefore, to confirm that LN was not the main cause of the clinical proteinuria, we investigated the GBM using a different method.
For further evaluation, we observed the GBM in all three biopsy specimens using LV-SEM (Hitachi Tabletop microscope TM4000; Hitachi High-Technologies Corp., Tokyo, Japan). In the first renal biopsy at the age of 48 years, LV-SEM of glomeruli retrieved from formalin-fixed paraffin-embedded tissue (PAM stain) revealed extensive and numerous subepithelial holes where deposits were thought to have been present. Additionally, well-developed GBM material formed spikes around the holes (Fig. 2a1). However, these holes were not found on the glomerular capillary luminal side (Fig. 2a2). This finding corresponded to Ehrenreich-Churg stage II membranous nephropathy (MN). The second renal biopsy at the age of 54 years showed a well-developed GBM reaction surrounding the holes where deposits might have been present; this finding was equivalent to Ehrenreich-Churg stage III MN (Fig. 2b1). Epithelium had formed and covered holes found in the first renal biopsy tissue, and it was difficult to see holes when looking down from the subepithelial side (Fig. 2b1). The GBM of the glomerular capillary lumina was almost covered by basement membrane material, and holes were still only partially open (Fig. 2b2). The third renal biopsy at the age of 57 years exhibited epithelium covered by newly formed GBM material, with openings in the GBM inward toward the glomerular capillary lumen (Fig. 2c1, c2). We speculated that the holes in the glomerular capillary luminal side might emerge when immune complex deposits in the GBM wash out.
In studying the third renal biopsy specimen, we also drew a comparison between the IF findings of the scattered distribution of the deposits and the LV-SEM findings. We stained frozen sections for IF with PAM and examined them with LV-SEM. We compared and observed the same glomeruli (Fig. 3). No IgG staining was confirmed using IF, which suggested that no deposits were present in the GBM (Fig. 3a). However, many cavities were confirmed using LV-SEM (FIG. 3b). Therefore, it was considered that no deposit was present in the many holes, and it was presumed that washout of the immune complex deposits occurred in the membranous LN. Overall, further observation of the GBM with LV-SEM confirmed resolution of class V LN. This case was similar to stage IV MN according to the Ehrenreich-Churg staging criteria.
A case report by Nonaka et al. [12] described the conventional TEM assessment of subepithelial deposits in a patient with mild membranous LN. However, few cases of LN evaluated using LV-SEM in which the loss of immune complex deposits was discovered have been reported. Clinicians emphasize IgG deposition in the diagnosis of LN. Many clinicians tend to consider that LN is highly unlikely if IgG is negative using IF examination. In the present case, however, the diagnosis of LN was confirmed in the first and second renal biopsies.
This is our first experience of a case in which the pathological findings were presumed to indicate a state of resolution of class V LN, and we thought that this was a highly contradictory finding. We had doubts regarding whether the histopathological findings of LN disappear (as in common MN) as the disease activity of SLE decreases.
Discussion/Conclusion
In the present study, we found that membranous LN diminished or resolved over the course of the three renal biopsies. To help clarify this process, we evaluated the patient's kidney biopsy tissue using LV-SEM, which allows for observation of both sides of the GBM. By studying the three-dimensional structure of the GBM using LV-SEM, we confirmed the formation of holes on the glomerular capillary luminal side. From these findings, we suspected that the same pathology of the membrane washout phenomenon that occurs in MN occurred in our patient with LN.
LV-SEM sometimes outperforms the conventional technique, TEM. TEM is the superior technique for investigating cross-sectional images of various components in glomeruli; however, performing three-dimensional and whole/wide observations using ultrathin sections is difficult because of the limitation of the observable size. LV-SEM can be used to evaluate the three-dimensional ultrastructural changes of the glomerular extracellular matrices in the same specimen used for LM. It thus provides more detailed three-dimensional information [8, 9]. Therefore, to review the morphological alterations of the glomeruli in a three-dimensional, broad area, we examined the LM slides of the renal biopsy specimens using LV-SEM.
LV-SEM examination of the first biopsy revealed many openings or holes in the subepithelium, consistent with the LM, IF, and TEM findings. The second renal biopsy showed a well-developed GBM reaction surrounding the openings or holes with overlying foot process effacement. These LV-SEM results were almost identical to those of TEM. The third renal biopsy showed openings on the thickened GBM inward toward the glomerular capillary lumina and loss of the electron density of the deposits in TEM. We confirmed the findings of some openings or holes in the GBM on the luminal side of the vessel using LV-SEM. Thus, we suspected that the deposits were washed out through these holes. In other words, the findings we confirmed using LV-SEM might result from washout of the immune complexes (only the cavity remained after washout). This concept allows for the possibility of finding IgG positivity on IF, which can be said to be an essential marker of LN. IgG was negative using IF in the tissue from the third renal biopsy in this patient.
Furthermore, it is possible that LV-SEM might be useful for monitoring disease, in contrast to interpreting potentially challenging serological results. An example is M-type phospholipase A2 receptor (PLA2R)-negative MN. PLA2R-negative secondary MN is generally characterized by the irregular distribution and size of subepithelial deposits and the presence of irregular subendothelial and mesangial deposits in glomeruli. We believe that there may be some difference in the GBM of PRA2R-positive or -negative MN evaluated in detail using LV-SEM.
The Ehrenreich-Churg classification divides MN into four pathological stages according to the state of immune complex deposition and change in the GBM [13]. Stage IV MN is characterized by loss of the electron density of the deposits, transition to a “washout” state, and development of electron-lucent zones within an irregularly thickened GBM [13]. Furthermore, the GBM recovers to an almost normal morphology in stage V MN [14]. The GBM returns to its normal form without deposition or thickening in the state of washed-out MN. In the present case, however, LM did not show findings consistent with normalization of the GBM morphology, similar to the washout image seen in stage IV or V MN, and changes such as thickening and spike formation persisted. However, IgG and C3 deposits cannot be seen using IF staining. TEM also exhibited few deposits. This series of pathophysiological findings has been confirmed by observations on resolving glomerulopathy in serial allograft biopsies [15].
Based on these results, we postulated a pathological process beginning with LN that caused deposition of immune complexes on the GBM. A decrease in LN activity then led to loss of these deposits as the disease progressed to a state of stage V MN washout, which results in a bubbly appearance. That is, despite resolution of LN, LM showed a remarkable change in the GBM. When LM shows noticeable changes in the GBM and specific clinical findings are present (excessive urinary protein), clinicians will usually think that the cause is LN.
The opening on the GBM is normally covered by vascular endothelium. However, in MN, complement complexes might injure the GBM by inducing the production of reactive oxygen species, thus altering the membrane structure [16]. At that time, a large proportion of the immune complex might have passed through the GBM from the glomerular capillary luminal side toward the epithelial side and nephrosis developed. We suspected that in the present case, this backward event (from the epithelial side toward the glomerular capillary luminal side) could have occurred during the LN washout phase. In other words, we suspected the possibility that these holes observed on the glomerular capillary luminal side were formed when the immune complexes were washed out.
In conclusion, our patient exhibited a loss of LN activity and a change to a state of resolution of class V LN. Renal biopsy revealed negative conversion of IgG on IF, and spikes and domes were present in the GBM on LM. We believe that the evaluation of three-dimensional structural alterations in GBM using LV-SEM might be a useful approach for assessing variation in renal biopsies over time.
Statement of Ethics
This study was conducted according to the guidelines laid down in the World Medical Association Declaration of Helsinki. Informed consent was obtained from the patient described in this case report, and the consent allowed their data to be stored, as required by the Hiroshima University Hospital. Written consent to publish this information was obtained from the patient (images and publication).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not funded by any third party.
Author Contributions
M.Y., S.H., and T.D. contributed to the data collection. S.H. and T.M. designed the research. Y.M. and A.S. evaluated the pathological tissue. M.Y. and S.H. performed the primary manuscript preparation. M.Y., S.H., T.D., and T.M. wrote the paper. T.M. has primary responsibility for the final content. M.Y., S.H., T.D., Y.M., and A.S. reviewed the paper and revised it critically. All authors read and approved the final manuscript.
Acknowledgments
We thank Angela Morben, DVM, ELS, and Andrea Baird, MD, from Edanz Group (https://en-author-services.edanzgroup.com/), for editing drafts of the manuscript.
Fig. 1 Renal biopsy findings. a First renal biopsy. a1 LM revealed that the basement membrane was thickened and exhibited mainly spikes (red arrowheads) (PAM stain). Scale bar, 25 μm. a2 IF staining demonstrated coarsely granular deposits of IgG, C3, and C1q in the capillary walls (IF microscopy, IgG, C3, C1q; ×200). a3 TEM showed abundant subepithelial deposits. The pattern was equivalent to Ehrenreich-Churg stage II MN. Scale bar, 2 µm (TEM). b Second renal biopsy. b1 The basement membrane showed a global increase in thickening and a bubbly appearance on LM (red arrowheads). This appearance was comparable with Ehrenreich-Churg stage III MN (PAM stain). Scale bar, 50 μm. b2 IF exhibited coarsely granular deposits of IgG, C3, and C1q in the capillary basement membrane, as in the previous examination (IF microscopy, IgG, C3, C1q; ×200). b3 TEM examination showed that the dense deposits were smaller and had been partly resorbed. A well-developed basement membrane reaction surrounded the deposits with overlying foot process effacement. Scale bar, 2 µm (TEM). c Third renal biopsy. c1 The basement membrane was thickened and exhibited a general meandering-like wrinkling pattern as seen on LM. The bubbly appearance was the same as in the second biopsies (PAM stain). Scale bar, 50 μm. c2 IF showed almost negative conversion of IgG and negative C3 and C1q (IF microscopy, IgG, C3, C1q; ×200). c3 On TEM, the basement membrane showed global thickening, wrinkling, and podocyte foot process effacement. The electron density of the deposits was unclear. Scale bar, 2 µm (TEM). C, complement; IF, immunofluorescence; IgG, immunoglobulin G; LM, light microscopy; MN, membranous nephropathy; PAM, periodic acid methenamine silver; TEM, transmission electron microscopy.
Fig. 2 Renal biopsy findings using LV-SEM. a First renal biopsy. a1 An image from the epithelial side of the GBM. Basement membrane material accumulated between many holes (deposit-like appearance) and projected into the urinary space as “spikes” (red arrowheads). The holes were not covered with basement membrane. Scale bar, 2.5 μm. a2 An image from the glomerular capillary lumina. The GBM of the glomerular capillary luminal side was covered by the material of the basement membrane, and no opening was seen (blue arrowheads). Scale bar, 2.5 μm. b Second renal biopsy. b1 An image from the epithelial side of the GBM. Intramembranous holes were observed. These holes (deposit-like appearance) were surrounded by well-developed basement membrane material (red arrowheads). In the subepithelium of the GBM, basement membrane material was newly formed on the holes, and the holes seen in a1 could not be confirmed from the epithelium side view. Scale bar, 5 μm. b2 An image from the glomerular capillary lumina. The GBM of the glomerular capillary lumina was almost covered by basement membrane material, and holes were still only partially open. Scale bar, 2.5 μm. c Third renal biopsy. c1 An image from the epithelial side of the GBM. Thickening of the basement membrane was still present. Vacuolation was present in potential spaces where the deposits might have been. The holes on the epithelium side shown in a1 were hardly observed. Scale bar, 2.5 μm. c2 An image from the glomerular capillary lumina. In contrast to c1, openings were present on the glomerular basement membrane inward toward the glomerular capillary lumina (blue arrowheads). Electron-lucent-like areas probably represented resorption of prior subepithelial immune complexes. Scale bar, 5 μm. GBM, glomerular basement membrane; LV-SEM, low-vacuum scanning electron microscopy.
Fig. 3 Comparison between IF microscopy and LV-SEM findings. a PAM stain of an IF-stained specimen. IF staining seemed to be almost nonexistent (red arrowhead and circle). b LV-SEM findings did not clearly confirm the immune complex deposition in the area (red arrowhead and circle). Examination of the site with LV-SEM indicated washout of the immune complex deposition. IF, immunofluorescence; LV-SEM, low-vacuum scanning electron microscopy; PAM, periodic acid methenamine silver.
Table 1 Patient's laboratory results upon admission at the age of 57 years
Parameter Value Reference range
Urine
pH 5.5 5.0–6.5
Red blood cells, /HPF 0–1 <5
Fatty casts, /WF 1–4 Negative
Epithelial casts, /WF 1–4 Negative
Urine protein/creatinine ratio, g/g 2.68 <0.15
N-acetyl-β-D-glucosaminidase, IU/L 13.2 0.7–11.2
β2-Microglobulin, µg/L 0.75 <230
Blood
Leukocyte count, /µL 4,750 4,500–9,000
Lymphocytes, /µL 940 1,200–3,690
Hemoglobin, g/dL 11.9 13.6–17.0
Platelet count, ×104/µL 20.7 14–36
Urea nitrogen, mg/dL 21.4 8.0–22.0
Creatinine, mg/dL 0.85 0.60–1.10
Estimated GFR, mL/min/1.73 m2 53 >90
Uric acid, mg/dL 6.0 3.6–7.0
Total protein, g/dL 6.2 6.7–8.3
Albumin, g/dL 3.7 4.0–5.0
Sodium, mEq/L 140 138–146
Potassium, mEq/L 5.3 3.6–4.9
Chloride, mEq/L 108 99–109
Corrected serum calcium, mg/dL 8.8 8.6–10.4
Phosphate, mg/dL 3.5 2.5–4.7
C-reactive protein, mg/dL 0.07 <0.30
CH50, CH50/mL 48.7 25–48
C3, mg/dL 98 65–135
C4, mg/dL 26 13–35
IgG, mg/dL 630 870–1,700
IgA, mg/dL 170 110–410
IgM, mg/dL 18 33–190
Anti-nuclear antibody ×320 <×40
(staining patterns) homologous, speckled
Anti-ssDNA antibody, IU/mL 2.8 <2.0
Anti-dsDNA antibody, IU/mL 5.8 <2.0
CH50, 50% hemolytic complement; dsDNA, double-stranded DNA; GFR, glomerular filtration rate; HPF, high-power field; Ig, immunoglobulin; ssDNA, single-stranded DNA; WF, whole field. | PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33708798 | 19,404,881 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Protein urine present'. | Low-Vacuum Scanning Electron Microscopy to Assess Histopathological Resolution of Class V Lupus Nephritis: A Case Report.
Lupus nephritis (LN) is most frequently associated with poor outcomes in patients with systemic lupus erythematosus (SLE). LN manifests as histopathological changes in the kidney caused by immune complex formation and deposition. In particular, immunoglobulin G (IgG) deposits are frequently observed by immunofluorescence staining, which helps to establish the diagnosis of LN. In this case report, we describe a 57-year-old woman with SLE who had been undergoing treatment on an outpatient basis for 11 years. Her first and second renal biopsies revealed class V LN with a coarsely granular pattern of IgG deposition in the peripheral capillary walls. However, her third renal biopsy showed no IgG deposition, which indicated histopathological resolution of her class V LN. We used low-vacuum scanning electron microscopy (LV-SEM) to examine the three-dimensional structural alterations in her glomerular basement membranes. In this report, we describe findings that indicated resorption of epithelial deposits, that is, resolution of LN. The results of repeated kidney biopsies confirmed by LV-SEM suggested the possibility of a state unrelated to LN.
Introduction
Systemic lupus erythematosus (SLE) is a multiorgan, systemic autoimmune disease with clinical and serological heterogeneity [1]. Lupus nephritis (LN) is one of the most common and devastating manifestations of SLE. In approximately 50% of affected patients, SLE results in LN [2]. Although the overall mortality of patients with SLE has decreased remarkably in recent decades, renal disease remains the leading cause of death in these patients [3]. LN has histopathological diversity and is explained by immune complex deposition [4, 5]. Renal biopsy allows for evaluation of LN activity and determination of therapy based on histological features. Although individual patterns of immunofluorescence (IF) staining are highly variable, some general characteristics are applicable to all classes [4]. In more than 90% of patients with SLE, IF staining of the peripheral capillary wall or mesangial areas is seen microscopically. In particular, immunoglobulin G (IgG) deposits are observed using IF staining in almost every patient with LN [4, 6]. In most cases of LN, immune complexes in blood plasma are deposited on glomeruli, which can be seen using light microscopy (LM), IF, and transmission electron microscopy (TEM) [7].
In the present case, we performed three renal biopsies in 9 years. The first and second renal biopsies revealed IgG deposits in the peripheral capillary walls; however, the third renal biopsy showed no IgG deposits. Conventional renal biopsy paraffin sections stained with periodic acid methenamine silver (PAM) can be directly observed using low-vacuum scanning electron microscopy (LV-SEM). In conventional electron microscopy, only a small area can be viewed; however, LV-SEM enables scanning over broad areas of the specimen and in three dimensions under high magnification [8, 9]. We considered that evaluation using LV-SEM might be useful for the histopathological assessment of renal glomerular basement membrane (GBM) alterations. We therefore evaluated the two sides of the GBM using LV-SEM and examined the washout phenomenon of the membranous form of LN. We herein highlight the histopathological findings of this case.
Case Presentation
Clinical Information
A 57-year-old woman had presented with Raynaud's phenomenon and fever of unknown etiology at the age of 48 years. Laboratory analysis showed positive anti-nuclear autoantibody and renal insufficiency with proteinuria (1.33 g/g Cr). The titer of anti-double-stranded DNA autoantibody was slightly elevated (3.1 IU/mL). She was diagnosed with SLE in accordance with the Systemic Lupus International Collaborating Clinics criteria [10]. The patient's first renal biopsy was undertaken at this time. Examination of the biopsy specimen led to a diagnosis of class V LN in accordance with the World Health Organization classification [9]. According to this diagnosis, she was treated with oral prednisolone, and tacrolimus was added at the age of 49 years. These treatments were successful, and the urine protein level decreased remarkably 4 years after treatment was started (to around 0.3–0.4 g/g Cr). At the age of 53 years, she was treated with dose-reduced tacrolimus because the effectiveness of these treatments had been confirmed. Despite the slow improvement in her renal function, the severity of her proteinuria gradually increased during the 4 years since the first biopsy. We suspected recurrence, and she therefore underwent a second biopsy at the age of 54 years. This repeat biopsy also revealed class V LN. Based on these findings, mycophenolate mofetil at 1,250 mg/day was added to the treatment regimen.
At the age of 57 years, laboratory studies revealed low SLE activity with a normal complete blood count, normal complement protein levels, and an anti-double-stranded DNA antibody titer of 5.8 IU/mL; however, proteinuria was present (>2 g/g Cr) (Table 1). Therefore, she underwent a third renal biopsy at the age of 57 years. At this time, the patient's clinical course and immunological investigation indicated no progression of SLE. Because the pathological findings indicated negative conversion of IgG, we considered that the activity of LN had been lost. These pathological results could explain the decreased SLE activity, and the class V LN was presumed to have resolved.
The patient was subsequently treated with antihypertensive drugs with a focus on angiotensin II receptor antagonists. Following treatment, her proteinuria decreased to 0.5 g/g Cr.
Renal Biopsies
The patient's first renal biopsy was performed at the age of 48 years. Histopathological examination using LM revealed several foamy formations and a generalized diffuse thickening of the GBM, which manifested as prominent spikes on PAM silver staining (Fig. 1a1). On IF staining, coarsely granular deposits of IgG, C3, and C1q were evident in the capillary walls (Fig. 1a2). TEM revealed abundant subepithelial deposits lining all capillary loops (Fig. 1a3). The patient was diagnosed with LN class V according to the International Society of Nephrology/Renal Pathology Society classification.
The second biopsy at the age of 54 years revealed reduced spike formation and a bubbly appearance (stippling) under LM examination (Fig. 1b1). IF staining showed similar findings; coarsely granular deposits of IgG, C3, and C1q were evident in the capillary basement membrane (Fig. 1b2). On TEM, smaller electron-dense deposits than in the first renal biopsy suggested a resorptive process (Fig. 1b3). A well-developed GBM reaction surrounded the deposits with overlying foot process effacement. These findings also indicated type V LN.
The third biopsy at the age of 57 years revealed advanced glomerulosclerosis (5/25 glomeruli), and PAM silver staining exhibited a primarily bubbly appearance and dome patterns; the spikes had almost disappeared on LM examination (Fig. 1c1). Conversely, the IF findings showed a scattered distribution of the IgG deposits with negative C3 and C1q (Fig. 1c2). TEM also revealed a marked decrease in the electron density of the deposits that had been clearly seen in the previous two biopsies. Instead, GBM thickening and wrinkling were seen (Fig. 1c3). We doubted that the results of TEM and IF therefore differed from those of LM. Another remarkable finding on LM was arteriolar hyalinosis, which could be explained as arteriolopathy caused by calcineurin inhibitors. No evidence of calcineurin inhibitor toxicity such as striped interstitial fibrosis or tubular atrophy was observed. Tubular and interstitial lesions were attributed to the effect of renal sclerosis because of hypertension. The increase in urinary protein excretion could be explained by severe arterial sclerosis and calcineurin inhibitor-induced arteriolopathy rather than exacerbation of LN.
C4d is described as a byproduct of activation of the classical and lectin pathways. Because C4d acts as a positive marker for an immune complex-mediated mechanism in glomerular nephritis, C4d staining can be helpful in revealing immune complex deposition [11]. Unfortunately, we could not examine the C4d properties of the deposits using frozen sections because of a lack of additional tissue remaining in the block. Therefore, to confirm that LN was not the main cause of the clinical proteinuria, we investigated the GBM using a different method.
For further evaluation, we observed the GBM in all three biopsy specimens using LV-SEM (Hitachi Tabletop microscope TM4000; Hitachi High-Technologies Corp., Tokyo, Japan). In the first renal biopsy at the age of 48 years, LV-SEM of glomeruli retrieved from formalin-fixed paraffin-embedded tissue (PAM stain) revealed extensive and numerous subepithelial holes where deposits were thought to have been present. Additionally, well-developed GBM material formed spikes around the holes (Fig. 2a1). However, these holes were not found on the glomerular capillary luminal side (Fig. 2a2). This finding corresponded to Ehrenreich-Churg stage II membranous nephropathy (MN). The second renal biopsy at the age of 54 years showed a well-developed GBM reaction surrounding the holes where deposits might have been present; this finding was equivalent to Ehrenreich-Churg stage III MN (Fig. 2b1). Epithelium had formed and covered holes found in the first renal biopsy tissue, and it was difficult to see holes when looking down from the subepithelial side (Fig. 2b1). The GBM of the glomerular capillary lumina was almost covered by basement membrane material, and holes were still only partially open (Fig. 2b2). The third renal biopsy at the age of 57 years exhibited epithelium covered by newly formed GBM material, with openings in the GBM inward toward the glomerular capillary lumen (Fig. 2c1, c2). We speculated that the holes in the glomerular capillary luminal side might emerge when immune complex deposits in the GBM wash out.
In studying the third renal biopsy specimen, we also drew a comparison between the IF findings of the scattered distribution of the deposits and the LV-SEM findings. We stained frozen sections for IF with PAM and examined them with LV-SEM. We compared and observed the same glomeruli (Fig. 3). No IgG staining was confirmed using IF, which suggested that no deposits were present in the GBM (Fig. 3a). However, many cavities were confirmed using LV-SEM (FIG. 3b). Therefore, it was considered that no deposit was present in the many holes, and it was presumed that washout of the immune complex deposits occurred in the membranous LN. Overall, further observation of the GBM with LV-SEM confirmed resolution of class V LN. This case was similar to stage IV MN according to the Ehrenreich-Churg staging criteria.
A case report by Nonaka et al. [12] described the conventional TEM assessment of subepithelial deposits in a patient with mild membranous LN. However, few cases of LN evaluated using LV-SEM in which the loss of immune complex deposits was discovered have been reported. Clinicians emphasize IgG deposition in the diagnosis of LN. Many clinicians tend to consider that LN is highly unlikely if IgG is negative using IF examination. In the present case, however, the diagnosis of LN was confirmed in the first and second renal biopsies.
This is our first experience of a case in which the pathological findings were presumed to indicate a state of resolution of class V LN, and we thought that this was a highly contradictory finding. We had doubts regarding whether the histopathological findings of LN disappear (as in common MN) as the disease activity of SLE decreases.
Discussion/Conclusion
In the present study, we found that membranous LN diminished or resolved over the course of the three renal biopsies. To help clarify this process, we evaluated the patient's kidney biopsy tissue using LV-SEM, which allows for observation of both sides of the GBM. By studying the three-dimensional structure of the GBM using LV-SEM, we confirmed the formation of holes on the glomerular capillary luminal side. From these findings, we suspected that the same pathology of the membrane washout phenomenon that occurs in MN occurred in our patient with LN.
LV-SEM sometimes outperforms the conventional technique, TEM. TEM is the superior technique for investigating cross-sectional images of various components in glomeruli; however, performing three-dimensional and whole/wide observations using ultrathin sections is difficult because of the limitation of the observable size. LV-SEM can be used to evaluate the three-dimensional ultrastructural changes of the glomerular extracellular matrices in the same specimen used for LM. It thus provides more detailed three-dimensional information [8, 9]. Therefore, to review the morphological alterations of the glomeruli in a three-dimensional, broad area, we examined the LM slides of the renal biopsy specimens using LV-SEM.
LV-SEM examination of the first biopsy revealed many openings or holes in the subepithelium, consistent with the LM, IF, and TEM findings. The second renal biopsy showed a well-developed GBM reaction surrounding the openings or holes with overlying foot process effacement. These LV-SEM results were almost identical to those of TEM. The third renal biopsy showed openings on the thickened GBM inward toward the glomerular capillary lumina and loss of the electron density of the deposits in TEM. We confirmed the findings of some openings or holes in the GBM on the luminal side of the vessel using LV-SEM. Thus, we suspected that the deposits were washed out through these holes. In other words, the findings we confirmed using LV-SEM might result from washout of the immune complexes (only the cavity remained after washout). This concept allows for the possibility of finding IgG positivity on IF, which can be said to be an essential marker of LN. IgG was negative using IF in the tissue from the third renal biopsy in this patient.
Furthermore, it is possible that LV-SEM might be useful for monitoring disease, in contrast to interpreting potentially challenging serological results. An example is M-type phospholipase A2 receptor (PLA2R)-negative MN. PLA2R-negative secondary MN is generally characterized by the irregular distribution and size of subepithelial deposits and the presence of irregular subendothelial and mesangial deposits in glomeruli. We believe that there may be some difference in the GBM of PRA2R-positive or -negative MN evaluated in detail using LV-SEM.
The Ehrenreich-Churg classification divides MN into four pathological stages according to the state of immune complex deposition and change in the GBM [13]. Stage IV MN is characterized by loss of the electron density of the deposits, transition to a “washout” state, and development of electron-lucent zones within an irregularly thickened GBM [13]. Furthermore, the GBM recovers to an almost normal morphology in stage V MN [14]. The GBM returns to its normal form without deposition or thickening in the state of washed-out MN. In the present case, however, LM did not show findings consistent with normalization of the GBM morphology, similar to the washout image seen in stage IV or V MN, and changes such as thickening and spike formation persisted. However, IgG and C3 deposits cannot be seen using IF staining. TEM also exhibited few deposits. This series of pathophysiological findings has been confirmed by observations on resolving glomerulopathy in serial allograft biopsies [15].
Based on these results, we postulated a pathological process beginning with LN that caused deposition of immune complexes on the GBM. A decrease in LN activity then led to loss of these deposits as the disease progressed to a state of stage V MN washout, which results in a bubbly appearance. That is, despite resolution of LN, LM showed a remarkable change in the GBM. When LM shows noticeable changes in the GBM and specific clinical findings are present (excessive urinary protein), clinicians will usually think that the cause is LN.
The opening on the GBM is normally covered by vascular endothelium. However, in MN, complement complexes might injure the GBM by inducing the production of reactive oxygen species, thus altering the membrane structure [16]. At that time, a large proportion of the immune complex might have passed through the GBM from the glomerular capillary luminal side toward the epithelial side and nephrosis developed. We suspected that in the present case, this backward event (from the epithelial side toward the glomerular capillary luminal side) could have occurred during the LN washout phase. In other words, we suspected the possibility that these holes observed on the glomerular capillary luminal side were formed when the immune complexes were washed out.
In conclusion, our patient exhibited a loss of LN activity and a change to a state of resolution of class V LN. Renal biopsy revealed negative conversion of IgG on IF, and spikes and domes were present in the GBM on LM. We believe that the evaluation of three-dimensional structural alterations in GBM using LV-SEM might be a useful approach for assessing variation in renal biopsies over time.
Statement of Ethics
This study was conducted according to the guidelines laid down in the World Medical Association Declaration of Helsinki. Informed consent was obtained from the patient described in this case report, and the consent allowed their data to be stored, as required by the Hiroshima University Hospital. Written consent to publish this information was obtained from the patient (images and publication).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not funded by any third party.
Author Contributions
M.Y., S.H., and T.D. contributed to the data collection. S.H. and T.M. designed the research. Y.M. and A.S. evaluated the pathological tissue. M.Y. and S.H. performed the primary manuscript preparation. M.Y., S.H., T.D., and T.M. wrote the paper. T.M. has primary responsibility for the final content. M.Y., S.H., T.D., Y.M., and A.S. reviewed the paper and revised it critically. All authors read and approved the final manuscript.
Acknowledgments
We thank Angela Morben, DVM, ELS, and Andrea Baird, MD, from Edanz Group (https://en-author-services.edanzgroup.com/), for editing drafts of the manuscript.
Fig. 1 Renal biopsy findings. a First renal biopsy. a1 LM revealed that the basement membrane was thickened and exhibited mainly spikes (red arrowheads) (PAM stain). Scale bar, 25 μm. a2 IF staining demonstrated coarsely granular deposits of IgG, C3, and C1q in the capillary walls (IF microscopy, IgG, C3, C1q; ×200). a3 TEM showed abundant subepithelial deposits. The pattern was equivalent to Ehrenreich-Churg stage II MN. Scale bar, 2 µm (TEM). b Second renal biopsy. b1 The basement membrane showed a global increase in thickening and a bubbly appearance on LM (red arrowheads). This appearance was comparable with Ehrenreich-Churg stage III MN (PAM stain). Scale bar, 50 μm. b2 IF exhibited coarsely granular deposits of IgG, C3, and C1q in the capillary basement membrane, as in the previous examination (IF microscopy, IgG, C3, C1q; ×200). b3 TEM examination showed that the dense deposits were smaller and had been partly resorbed. A well-developed basement membrane reaction surrounded the deposits with overlying foot process effacement. Scale bar, 2 µm (TEM). c Third renal biopsy. c1 The basement membrane was thickened and exhibited a general meandering-like wrinkling pattern as seen on LM. The bubbly appearance was the same as in the second biopsies (PAM stain). Scale bar, 50 μm. c2 IF showed almost negative conversion of IgG and negative C3 and C1q (IF microscopy, IgG, C3, C1q; ×200). c3 On TEM, the basement membrane showed global thickening, wrinkling, and podocyte foot process effacement. The electron density of the deposits was unclear. Scale bar, 2 µm (TEM). C, complement; IF, immunofluorescence; IgG, immunoglobulin G; LM, light microscopy; MN, membranous nephropathy; PAM, periodic acid methenamine silver; TEM, transmission electron microscopy.
Fig. 2 Renal biopsy findings using LV-SEM. a First renal biopsy. a1 An image from the epithelial side of the GBM. Basement membrane material accumulated between many holes (deposit-like appearance) and projected into the urinary space as “spikes” (red arrowheads). The holes were not covered with basement membrane. Scale bar, 2.5 μm. a2 An image from the glomerular capillary lumina. The GBM of the glomerular capillary luminal side was covered by the material of the basement membrane, and no opening was seen (blue arrowheads). Scale bar, 2.5 μm. b Second renal biopsy. b1 An image from the epithelial side of the GBM. Intramembranous holes were observed. These holes (deposit-like appearance) were surrounded by well-developed basement membrane material (red arrowheads). In the subepithelium of the GBM, basement membrane material was newly formed on the holes, and the holes seen in a1 could not be confirmed from the epithelium side view. Scale bar, 5 μm. b2 An image from the glomerular capillary lumina. The GBM of the glomerular capillary lumina was almost covered by basement membrane material, and holes were still only partially open. Scale bar, 2.5 μm. c Third renal biopsy. c1 An image from the epithelial side of the GBM. Thickening of the basement membrane was still present. Vacuolation was present in potential spaces where the deposits might have been. The holes on the epithelium side shown in a1 were hardly observed. Scale bar, 2.5 μm. c2 An image from the glomerular capillary lumina. In contrast to c1, openings were present on the glomerular basement membrane inward toward the glomerular capillary lumina (blue arrowheads). Electron-lucent-like areas probably represented resorption of prior subepithelial immune complexes. Scale bar, 5 μm. GBM, glomerular basement membrane; LV-SEM, low-vacuum scanning electron microscopy.
Fig. 3 Comparison between IF microscopy and LV-SEM findings. a PAM stain of an IF-stained specimen. IF staining seemed to be almost nonexistent (red arrowhead and circle). b LV-SEM findings did not clearly confirm the immune complex deposition in the area (red arrowhead and circle). Examination of the site with LV-SEM indicated washout of the immune complex deposition. IF, immunofluorescence; LV-SEM, low-vacuum scanning electron microscopy; PAM, periodic acid methenamine silver.
Table 1 Patient's laboratory results upon admission at the age of 57 years
Parameter Value Reference range
Urine
pH 5.5 5.0–6.5
Red blood cells, /HPF 0–1 <5
Fatty casts, /WF 1–4 Negative
Epithelial casts, /WF 1–4 Negative
Urine protein/creatinine ratio, g/g 2.68 <0.15
N-acetyl-β-D-glucosaminidase, IU/L 13.2 0.7–11.2
β2-Microglobulin, µg/L 0.75 <230
Blood
Leukocyte count, /µL 4,750 4,500–9,000
Lymphocytes, /µL 940 1,200–3,690
Hemoglobin, g/dL 11.9 13.6–17.0
Platelet count, ×104/µL 20.7 14–36
Urea nitrogen, mg/dL 21.4 8.0–22.0
Creatinine, mg/dL 0.85 0.60–1.10
Estimated GFR, mL/min/1.73 m2 53 >90
Uric acid, mg/dL 6.0 3.6–7.0
Total protein, g/dL 6.2 6.7–8.3
Albumin, g/dL 3.7 4.0–5.0
Sodium, mEq/L 140 138–146
Potassium, mEq/L 5.3 3.6–4.9
Chloride, mEq/L 108 99–109
Corrected serum calcium, mg/dL 8.8 8.6–10.4
Phosphate, mg/dL 3.5 2.5–4.7
C-reactive protein, mg/dL 0.07 <0.30
CH50, CH50/mL 48.7 25–48
C3, mg/dL 98 65–135
C4, mg/dL 26 13–35
IgG, mg/dL 630 870–1,700
IgA, mg/dL 170 110–410
IgM, mg/dL 18 33–190
Anti-nuclear antibody ×320 <×40
(staining patterns) homologous, speckled
Anti-ssDNA antibody, IU/mL 2.8 <2.0
Anti-dsDNA antibody, IU/mL 5.8 <2.0
CH50, 50% hemolytic complement; dsDNA, double-stranded DNA; GFR, glomerular filtration rate; HPF, high-power field; Ig, immunoglobulin; ssDNA, single-stranded DNA; WF, whole field. | PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33708798 | 19,404,881 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vascular hyalinosis'. | Low-Vacuum Scanning Electron Microscopy to Assess Histopathological Resolution of Class V Lupus Nephritis: A Case Report.
Lupus nephritis (LN) is most frequently associated with poor outcomes in patients with systemic lupus erythematosus (SLE). LN manifests as histopathological changes in the kidney caused by immune complex formation and deposition. In particular, immunoglobulin G (IgG) deposits are frequently observed by immunofluorescence staining, which helps to establish the diagnosis of LN. In this case report, we describe a 57-year-old woman with SLE who had been undergoing treatment on an outpatient basis for 11 years. Her first and second renal biopsies revealed class V LN with a coarsely granular pattern of IgG deposition in the peripheral capillary walls. However, her third renal biopsy showed no IgG deposition, which indicated histopathological resolution of her class V LN. We used low-vacuum scanning electron microscopy (LV-SEM) to examine the three-dimensional structural alterations in her glomerular basement membranes. In this report, we describe findings that indicated resorption of epithelial deposits, that is, resolution of LN. The results of repeated kidney biopsies confirmed by LV-SEM suggested the possibility of a state unrelated to LN.
Introduction
Systemic lupus erythematosus (SLE) is a multiorgan, systemic autoimmune disease with clinical and serological heterogeneity [1]. Lupus nephritis (LN) is one of the most common and devastating manifestations of SLE. In approximately 50% of affected patients, SLE results in LN [2]. Although the overall mortality of patients with SLE has decreased remarkably in recent decades, renal disease remains the leading cause of death in these patients [3]. LN has histopathological diversity and is explained by immune complex deposition [4, 5]. Renal biopsy allows for evaluation of LN activity and determination of therapy based on histological features. Although individual patterns of immunofluorescence (IF) staining are highly variable, some general characteristics are applicable to all classes [4]. In more than 90% of patients with SLE, IF staining of the peripheral capillary wall or mesangial areas is seen microscopically. In particular, immunoglobulin G (IgG) deposits are observed using IF staining in almost every patient with LN [4, 6]. In most cases of LN, immune complexes in blood plasma are deposited on glomeruli, which can be seen using light microscopy (LM), IF, and transmission electron microscopy (TEM) [7].
In the present case, we performed three renal biopsies in 9 years. The first and second renal biopsies revealed IgG deposits in the peripheral capillary walls; however, the third renal biopsy showed no IgG deposits. Conventional renal biopsy paraffin sections stained with periodic acid methenamine silver (PAM) can be directly observed using low-vacuum scanning electron microscopy (LV-SEM). In conventional electron microscopy, only a small area can be viewed; however, LV-SEM enables scanning over broad areas of the specimen and in three dimensions under high magnification [8, 9]. We considered that evaluation using LV-SEM might be useful for the histopathological assessment of renal glomerular basement membrane (GBM) alterations. We therefore evaluated the two sides of the GBM using LV-SEM and examined the washout phenomenon of the membranous form of LN. We herein highlight the histopathological findings of this case.
Case Presentation
Clinical Information
A 57-year-old woman had presented with Raynaud's phenomenon and fever of unknown etiology at the age of 48 years. Laboratory analysis showed positive anti-nuclear autoantibody and renal insufficiency with proteinuria (1.33 g/g Cr). The titer of anti-double-stranded DNA autoantibody was slightly elevated (3.1 IU/mL). She was diagnosed with SLE in accordance with the Systemic Lupus International Collaborating Clinics criteria [10]. The patient's first renal biopsy was undertaken at this time. Examination of the biopsy specimen led to a diagnosis of class V LN in accordance with the World Health Organization classification [9]. According to this diagnosis, she was treated with oral prednisolone, and tacrolimus was added at the age of 49 years. These treatments were successful, and the urine protein level decreased remarkably 4 years after treatment was started (to around 0.3–0.4 g/g Cr). At the age of 53 years, she was treated with dose-reduced tacrolimus because the effectiveness of these treatments had been confirmed. Despite the slow improvement in her renal function, the severity of her proteinuria gradually increased during the 4 years since the first biopsy. We suspected recurrence, and she therefore underwent a second biopsy at the age of 54 years. This repeat biopsy also revealed class V LN. Based on these findings, mycophenolate mofetil at 1,250 mg/day was added to the treatment regimen.
At the age of 57 years, laboratory studies revealed low SLE activity with a normal complete blood count, normal complement protein levels, and an anti-double-stranded DNA antibody titer of 5.8 IU/mL; however, proteinuria was present (>2 g/g Cr) (Table 1). Therefore, she underwent a third renal biopsy at the age of 57 years. At this time, the patient's clinical course and immunological investigation indicated no progression of SLE. Because the pathological findings indicated negative conversion of IgG, we considered that the activity of LN had been lost. These pathological results could explain the decreased SLE activity, and the class V LN was presumed to have resolved.
The patient was subsequently treated with antihypertensive drugs with a focus on angiotensin II receptor antagonists. Following treatment, her proteinuria decreased to 0.5 g/g Cr.
Renal Biopsies
The patient's first renal biopsy was performed at the age of 48 years. Histopathological examination using LM revealed several foamy formations and a generalized diffuse thickening of the GBM, which manifested as prominent spikes on PAM silver staining (Fig. 1a1). On IF staining, coarsely granular deposits of IgG, C3, and C1q were evident in the capillary walls (Fig. 1a2). TEM revealed abundant subepithelial deposits lining all capillary loops (Fig. 1a3). The patient was diagnosed with LN class V according to the International Society of Nephrology/Renal Pathology Society classification.
The second biopsy at the age of 54 years revealed reduced spike formation and a bubbly appearance (stippling) under LM examination (Fig. 1b1). IF staining showed similar findings; coarsely granular deposits of IgG, C3, and C1q were evident in the capillary basement membrane (Fig. 1b2). On TEM, smaller electron-dense deposits than in the first renal biopsy suggested a resorptive process (Fig. 1b3). A well-developed GBM reaction surrounded the deposits with overlying foot process effacement. These findings also indicated type V LN.
The third biopsy at the age of 57 years revealed advanced glomerulosclerosis (5/25 glomeruli), and PAM silver staining exhibited a primarily bubbly appearance and dome patterns; the spikes had almost disappeared on LM examination (Fig. 1c1). Conversely, the IF findings showed a scattered distribution of the IgG deposits with negative C3 and C1q (Fig. 1c2). TEM also revealed a marked decrease in the electron density of the deposits that had been clearly seen in the previous two biopsies. Instead, GBM thickening and wrinkling were seen (Fig. 1c3). We doubted that the results of TEM and IF therefore differed from those of LM. Another remarkable finding on LM was arteriolar hyalinosis, which could be explained as arteriolopathy caused by calcineurin inhibitors. No evidence of calcineurin inhibitor toxicity such as striped interstitial fibrosis or tubular atrophy was observed. Tubular and interstitial lesions were attributed to the effect of renal sclerosis because of hypertension. The increase in urinary protein excretion could be explained by severe arterial sclerosis and calcineurin inhibitor-induced arteriolopathy rather than exacerbation of LN.
C4d is described as a byproduct of activation of the classical and lectin pathways. Because C4d acts as a positive marker for an immune complex-mediated mechanism in glomerular nephritis, C4d staining can be helpful in revealing immune complex deposition [11]. Unfortunately, we could not examine the C4d properties of the deposits using frozen sections because of a lack of additional tissue remaining in the block. Therefore, to confirm that LN was not the main cause of the clinical proteinuria, we investigated the GBM using a different method.
For further evaluation, we observed the GBM in all three biopsy specimens using LV-SEM (Hitachi Tabletop microscope TM4000; Hitachi High-Technologies Corp., Tokyo, Japan). In the first renal biopsy at the age of 48 years, LV-SEM of glomeruli retrieved from formalin-fixed paraffin-embedded tissue (PAM stain) revealed extensive and numerous subepithelial holes where deposits were thought to have been present. Additionally, well-developed GBM material formed spikes around the holes (Fig. 2a1). However, these holes were not found on the glomerular capillary luminal side (Fig. 2a2). This finding corresponded to Ehrenreich-Churg stage II membranous nephropathy (MN). The second renal biopsy at the age of 54 years showed a well-developed GBM reaction surrounding the holes where deposits might have been present; this finding was equivalent to Ehrenreich-Churg stage III MN (Fig. 2b1). Epithelium had formed and covered holes found in the first renal biopsy tissue, and it was difficult to see holes when looking down from the subepithelial side (Fig. 2b1). The GBM of the glomerular capillary lumina was almost covered by basement membrane material, and holes were still only partially open (Fig. 2b2). The third renal biopsy at the age of 57 years exhibited epithelium covered by newly formed GBM material, with openings in the GBM inward toward the glomerular capillary lumen (Fig. 2c1, c2). We speculated that the holes in the glomerular capillary luminal side might emerge when immune complex deposits in the GBM wash out.
In studying the third renal biopsy specimen, we also drew a comparison between the IF findings of the scattered distribution of the deposits and the LV-SEM findings. We stained frozen sections for IF with PAM and examined them with LV-SEM. We compared and observed the same glomeruli (Fig. 3). No IgG staining was confirmed using IF, which suggested that no deposits were present in the GBM (Fig. 3a). However, many cavities were confirmed using LV-SEM (FIG. 3b). Therefore, it was considered that no deposit was present in the many holes, and it was presumed that washout of the immune complex deposits occurred in the membranous LN. Overall, further observation of the GBM with LV-SEM confirmed resolution of class V LN. This case was similar to stage IV MN according to the Ehrenreich-Churg staging criteria.
A case report by Nonaka et al. [12] described the conventional TEM assessment of subepithelial deposits in a patient with mild membranous LN. However, few cases of LN evaluated using LV-SEM in which the loss of immune complex deposits was discovered have been reported. Clinicians emphasize IgG deposition in the diagnosis of LN. Many clinicians tend to consider that LN is highly unlikely if IgG is negative using IF examination. In the present case, however, the diagnosis of LN was confirmed in the first and second renal biopsies.
This is our first experience of a case in which the pathological findings were presumed to indicate a state of resolution of class V LN, and we thought that this was a highly contradictory finding. We had doubts regarding whether the histopathological findings of LN disappear (as in common MN) as the disease activity of SLE decreases.
Discussion/Conclusion
In the present study, we found that membranous LN diminished or resolved over the course of the three renal biopsies. To help clarify this process, we evaluated the patient's kidney biopsy tissue using LV-SEM, which allows for observation of both sides of the GBM. By studying the three-dimensional structure of the GBM using LV-SEM, we confirmed the formation of holes on the glomerular capillary luminal side. From these findings, we suspected that the same pathology of the membrane washout phenomenon that occurs in MN occurred in our patient with LN.
LV-SEM sometimes outperforms the conventional technique, TEM. TEM is the superior technique for investigating cross-sectional images of various components in glomeruli; however, performing three-dimensional and whole/wide observations using ultrathin sections is difficult because of the limitation of the observable size. LV-SEM can be used to evaluate the three-dimensional ultrastructural changes of the glomerular extracellular matrices in the same specimen used for LM. It thus provides more detailed three-dimensional information [8, 9]. Therefore, to review the morphological alterations of the glomeruli in a three-dimensional, broad area, we examined the LM slides of the renal biopsy specimens using LV-SEM.
LV-SEM examination of the first biopsy revealed many openings or holes in the subepithelium, consistent with the LM, IF, and TEM findings. The second renal biopsy showed a well-developed GBM reaction surrounding the openings or holes with overlying foot process effacement. These LV-SEM results were almost identical to those of TEM. The third renal biopsy showed openings on the thickened GBM inward toward the glomerular capillary lumina and loss of the electron density of the deposits in TEM. We confirmed the findings of some openings or holes in the GBM on the luminal side of the vessel using LV-SEM. Thus, we suspected that the deposits were washed out through these holes. In other words, the findings we confirmed using LV-SEM might result from washout of the immune complexes (only the cavity remained after washout). This concept allows for the possibility of finding IgG positivity on IF, which can be said to be an essential marker of LN. IgG was negative using IF in the tissue from the third renal biopsy in this patient.
Furthermore, it is possible that LV-SEM might be useful for monitoring disease, in contrast to interpreting potentially challenging serological results. An example is M-type phospholipase A2 receptor (PLA2R)-negative MN. PLA2R-negative secondary MN is generally characterized by the irregular distribution and size of subepithelial deposits and the presence of irregular subendothelial and mesangial deposits in glomeruli. We believe that there may be some difference in the GBM of PRA2R-positive or -negative MN evaluated in detail using LV-SEM.
The Ehrenreich-Churg classification divides MN into four pathological stages according to the state of immune complex deposition and change in the GBM [13]. Stage IV MN is characterized by loss of the electron density of the deposits, transition to a “washout” state, and development of electron-lucent zones within an irregularly thickened GBM [13]. Furthermore, the GBM recovers to an almost normal morphology in stage V MN [14]. The GBM returns to its normal form without deposition or thickening in the state of washed-out MN. In the present case, however, LM did not show findings consistent with normalization of the GBM morphology, similar to the washout image seen in stage IV or V MN, and changes such as thickening and spike formation persisted. However, IgG and C3 deposits cannot be seen using IF staining. TEM also exhibited few deposits. This series of pathophysiological findings has been confirmed by observations on resolving glomerulopathy in serial allograft biopsies [15].
Based on these results, we postulated a pathological process beginning with LN that caused deposition of immune complexes on the GBM. A decrease in LN activity then led to loss of these deposits as the disease progressed to a state of stage V MN washout, which results in a bubbly appearance. That is, despite resolution of LN, LM showed a remarkable change in the GBM. When LM shows noticeable changes in the GBM and specific clinical findings are present (excessive urinary protein), clinicians will usually think that the cause is LN.
The opening on the GBM is normally covered by vascular endothelium. However, in MN, complement complexes might injure the GBM by inducing the production of reactive oxygen species, thus altering the membrane structure [16]. At that time, a large proportion of the immune complex might have passed through the GBM from the glomerular capillary luminal side toward the epithelial side and nephrosis developed. We suspected that in the present case, this backward event (from the epithelial side toward the glomerular capillary luminal side) could have occurred during the LN washout phase. In other words, we suspected the possibility that these holes observed on the glomerular capillary luminal side were formed when the immune complexes were washed out.
In conclusion, our patient exhibited a loss of LN activity and a change to a state of resolution of class V LN. Renal biopsy revealed negative conversion of IgG on IF, and spikes and domes were present in the GBM on LM. We believe that the evaluation of three-dimensional structural alterations in GBM using LV-SEM might be a useful approach for assessing variation in renal biopsies over time.
Statement of Ethics
This study was conducted according to the guidelines laid down in the World Medical Association Declaration of Helsinki. Informed consent was obtained from the patient described in this case report, and the consent allowed their data to be stored, as required by the Hiroshima University Hospital. Written consent to publish this information was obtained from the patient (images and publication).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not funded by any third party.
Author Contributions
M.Y., S.H., and T.D. contributed to the data collection. S.H. and T.M. designed the research. Y.M. and A.S. evaluated the pathological tissue. M.Y. and S.H. performed the primary manuscript preparation. M.Y., S.H., T.D., and T.M. wrote the paper. T.M. has primary responsibility for the final content. M.Y., S.H., T.D., Y.M., and A.S. reviewed the paper and revised it critically. All authors read and approved the final manuscript.
Acknowledgments
We thank Angela Morben, DVM, ELS, and Andrea Baird, MD, from Edanz Group (https://en-author-services.edanzgroup.com/), for editing drafts of the manuscript.
Fig. 1 Renal biopsy findings. a First renal biopsy. a1 LM revealed that the basement membrane was thickened and exhibited mainly spikes (red arrowheads) (PAM stain). Scale bar, 25 μm. a2 IF staining demonstrated coarsely granular deposits of IgG, C3, and C1q in the capillary walls (IF microscopy, IgG, C3, C1q; ×200). a3 TEM showed abundant subepithelial deposits. The pattern was equivalent to Ehrenreich-Churg stage II MN. Scale bar, 2 µm (TEM). b Second renal biopsy. b1 The basement membrane showed a global increase in thickening and a bubbly appearance on LM (red arrowheads). This appearance was comparable with Ehrenreich-Churg stage III MN (PAM stain). Scale bar, 50 μm. b2 IF exhibited coarsely granular deposits of IgG, C3, and C1q in the capillary basement membrane, as in the previous examination (IF microscopy, IgG, C3, C1q; ×200). b3 TEM examination showed that the dense deposits were smaller and had been partly resorbed. A well-developed basement membrane reaction surrounded the deposits with overlying foot process effacement. Scale bar, 2 µm (TEM). c Third renal biopsy. c1 The basement membrane was thickened and exhibited a general meandering-like wrinkling pattern as seen on LM. The bubbly appearance was the same as in the second biopsies (PAM stain). Scale bar, 50 μm. c2 IF showed almost negative conversion of IgG and negative C3 and C1q (IF microscopy, IgG, C3, C1q; ×200). c3 On TEM, the basement membrane showed global thickening, wrinkling, and podocyte foot process effacement. The electron density of the deposits was unclear. Scale bar, 2 µm (TEM). C, complement; IF, immunofluorescence; IgG, immunoglobulin G; LM, light microscopy; MN, membranous nephropathy; PAM, periodic acid methenamine silver; TEM, transmission electron microscopy.
Fig. 2 Renal biopsy findings using LV-SEM. a First renal biopsy. a1 An image from the epithelial side of the GBM. Basement membrane material accumulated between many holes (deposit-like appearance) and projected into the urinary space as “spikes” (red arrowheads). The holes were not covered with basement membrane. Scale bar, 2.5 μm. a2 An image from the glomerular capillary lumina. The GBM of the glomerular capillary luminal side was covered by the material of the basement membrane, and no opening was seen (blue arrowheads). Scale bar, 2.5 μm. b Second renal biopsy. b1 An image from the epithelial side of the GBM. Intramembranous holes were observed. These holes (deposit-like appearance) were surrounded by well-developed basement membrane material (red arrowheads). In the subepithelium of the GBM, basement membrane material was newly formed on the holes, and the holes seen in a1 could not be confirmed from the epithelium side view. Scale bar, 5 μm. b2 An image from the glomerular capillary lumina. The GBM of the glomerular capillary lumina was almost covered by basement membrane material, and holes were still only partially open. Scale bar, 2.5 μm. c Third renal biopsy. c1 An image from the epithelial side of the GBM. Thickening of the basement membrane was still present. Vacuolation was present in potential spaces where the deposits might have been. The holes on the epithelium side shown in a1 were hardly observed. Scale bar, 2.5 μm. c2 An image from the glomerular capillary lumina. In contrast to c1, openings were present on the glomerular basement membrane inward toward the glomerular capillary lumina (blue arrowheads). Electron-lucent-like areas probably represented resorption of prior subepithelial immune complexes. Scale bar, 5 μm. GBM, glomerular basement membrane; LV-SEM, low-vacuum scanning electron microscopy.
Fig. 3 Comparison between IF microscopy and LV-SEM findings. a PAM stain of an IF-stained specimen. IF staining seemed to be almost nonexistent (red arrowhead and circle). b LV-SEM findings did not clearly confirm the immune complex deposition in the area (red arrowhead and circle). Examination of the site with LV-SEM indicated washout of the immune complex deposition. IF, immunofluorescence; LV-SEM, low-vacuum scanning electron microscopy; PAM, periodic acid methenamine silver.
Table 1 Patient's laboratory results upon admission at the age of 57 years
Parameter Value Reference range
Urine
pH 5.5 5.0–6.5
Red blood cells, /HPF 0–1 <5
Fatty casts, /WF 1–4 Negative
Epithelial casts, /WF 1–4 Negative
Urine protein/creatinine ratio, g/g 2.68 <0.15
N-acetyl-β-D-glucosaminidase, IU/L 13.2 0.7–11.2
β2-Microglobulin, µg/L 0.75 <230
Blood
Leukocyte count, /µL 4,750 4,500–9,000
Lymphocytes, /µL 940 1,200–3,690
Hemoglobin, g/dL 11.9 13.6–17.0
Platelet count, ×104/µL 20.7 14–36
Urea nitrogen, mg/dL 21.4 8.0–22.0
Creatinine, mg/dL 0.85 0.60–1.10
Estimated GFR, mL/min/1.73 m2 53 >90
Uric acid, mg/dL 6.0 3.6–7.0
Total protein, g/dL 6.2 6.7–8.3
Albumin, g/dL 3.7 4.0–5.0
Sodium, mEq/L 140 138–146
Potassium, mEq/L 5.3 3.6–4.9
Chloride, mEq/L 108 99–109
Corrected serum calcium, mg/dL 8.8 8.6–10.4
Phosphate, mg/dL 3.5 2.5–4.7
C-reactive protein, mg/dL 0.07 <0.30
CH50, CH50/mL 48.7 25–48
C3, mg/dL 98 65–135
C4, mg/dL 26 13–35
IgG, mg/dL 630 870–1,700
IgA, mg/dL 170 110–410
IgM, mg/dL 18 33–190
Anti-nuclear antibody ×320 <×40
(staining patterns) homologous, speckled
Anti-ssDNA antibody, IU/mL 2.8 <2.0
Anti-dsDNA antibody, IU/mL 5.8 <2.0
CH50, 50% hemolytic complement; dsDNA, double-stranded DNA; GFR, glomerular filtration rate; HPF, high-power field; Ig, immunoglobulin; ssDNA, single-stranded DNA; WF, whole field. | PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33708798 | 19,404,881 | 2021 |
What was the administration route of drug 'PREDNISOLONE'? | Low-Vacuum Scanning Electron Microscopy to Assess Histopathological Resolution of Class V Lupus Nephritis: A Case Report.
Lupus nephritis (LN) is most frequently associated with poor outcomes in patients with systemic lupus erythematosus (SLE). LN manifests as histopathological changes in the kidney caused by immune complex formation and deposition. In particular, immunoglobulin G (IgG) deposits are frequently observed by immunofluorescence staining, which helps to establish the diagnosis of LN. In this case report, we describe a 57-year-old woman with SLE who had been undergoing treatment on an outpatient basis for 11 years. Her first and second renal biopsies revealed class V LN with a coarsely granular pattern of IgG deposition in the peripheral capillary walls. However, her third renal biopsy showed no IgG deposition, which indicated histopathological resolution of her class V LN. We used low-vacuum scanning electron microscopy (LV-SEM) to examine the three-dimensional structural alterations in her glomerular basement membranes. In this report, we describe findings that indicated resorption of epithelial deposits, that is, resolution of LN. The results of repeated kidney biopsies confirmed by LV-SEM suggested the possibility of a state unrelated to LN.
Introduction
Systemic lupus erythematosus (SLE) is a multiorgan, systemic autoimmune disease with clinical and serological heterogeneity [1]. Lupus nephritis (LN) is one of the most common and devastating manifestations of SLE. In approximately 50% of affected patients, SLE results in LN [2]. Although the overall mortality of patients with SLE has decreased remarkably in recent decades, renal disease remains the leading cause of death in these patients [3]. LN has histopathological diversity and is explained by immune complex deposition [4, 5]. Renal biopsy allows for evaluation of LN activity and determination of therapy based on histological features. Although individual patterns of immunofluorescence (IF) staining are highly variable, some general characteristics are applicable to all classes [4]. In more than 90% of patients with SLE, IF staining of the peripheral capillary wall or mesangial areas is seen microscopically. In particular, immunoglobulin G (IgG) deposits are observed using IF staining in almost every patient with LN [4, 6]. In most cases of LN, immune complexes in blood plasma are deposited on glomeruli, which can be seen using light microscopy (LM), IF, and transmission electron microscopy (TEM) [7].
In the present case, we performed three renal biopsies in 9 years. The first and second renal biopsies revealed IgG deposits in the peripheral capillary walls; however, the third renal biopsy showed no IgG deposits. Conventional renal biopsy paraffin sections stained with periodic acid methenamine silver (PAM) can be directly observed using low-vacuum scanning electron microscopy (LV-SEM). In conventional electron microscopy, only a small area can be viewed; however, LV-SEM enables scanning over broad areas of the specimen and in three dimensions under high magnification [8, 9]. We considered that evaluation using LV-SEM might be useful for the histopathological assessment of renal glomerular basement membrane (GBM) alterations. We therefore evaluated the two sides of the GBM using LV-SEM and examined the washout phenomenon of the membranous form of LN. We herein highlight the histopathological findings of this case.
Case Presentation
Clinical Information
A 57-year-old woman had presented with Raynaud's phenomenon and fever of unknown etiology at the age of 48 years. Laboratory analysis showed positive anti-nuclear autoantibody and renal insufficiency with proteinuria (1.33 g/g Cr). The titer of anti-double-stranded DNA autoantibody was slightly elevated (3.1 IU/mL). She was diagnosed with SLE in accordance with the Systemic Lupus International Collaborating Clinics criteria [10]. The patient's first renal biopsy was undertaken at this time. Examination of the biopsy specimen led to a diagnosis of class V LN in accordance with the World Health Organization classification [9]. According to this diagnosis, she was treated with oral prednisolone, and tacrolimus was added at the age of 49 years. These treatments were successful, and the urine protein level decreased remarkably 4 years after treatment was started (to around 0.3–0.4 g/g Cr). At the age of 53 years, she was treated with dose-reduced tacrolimus because the effectiveness of these treatments had been confirmed. Despite the slow improvement in her renal function, the severity of her proteinuria gradually increased during the 4 years since the first biopsy. We suspected recurrence, and she therefore underwent a second biopsy at the age of 54 years. This repeat biopsy also revealed class V LN. Based on these findings, mycophenolate mofetil at 1,250 mg/day was added to the treatment regimen.
At the age of 57 years, laboratory studies revealed low SLE activity with a normal complete blood count, normal complement protein levels, and an anti-double-stranded DNA antibody titer of 5.8 IU/mL; however, proteinuria was present (>2 g/g Cr) (Table 1). Therefore, she underwent a third renal biopsy at the age of 57 years. At this time, the patient's clinical course and immunological investigation indicated no progression of SLE. Because the pathological findings indicated negative conversion of IgG, we considered that the activity of LN had been lost. These pathological results could explain the decreased SLE activity, and the class V LN was presumed to have resolved.
The patient was subsequently treated with antihypertensive drugs with a focus on angiotensin II receptor antagonists. Following treatment, her proteinuria decreased to 0.5 g/g Cr.
Renal Biopsies
The patient's first renal biopsy was performed at the age of 48 years. Histopathological examination using LM revealed several foamy formations and a generalized diffuse thickening of the GBM, which manifested as prominent spikes on PAM silver staining (Fig. 1a1). On IF staining, coarsely granular deposits of IgG, C3, and C1q were evident in the capillary walls (Fig. 1a2). TEM revealed abundant subepithelial deposits lining all capillary loops (Fig. 1a3). The patient was diagnosed with LN class V according to the International Society of Nephrology/Renal Pathology Society classification.
The second biopsy at the age of 54 years revealed reduced spike formation and a bubbly appearance (stippling) under LM examination (Fig. 1b1). IF staining showed similar findings; coarsely granular deposits of IgG, C3, and C1q were evident in the capillary basement membrane (Fig. 1b2). On TEM, smaller electron-dense deposits than in the first renal biopsy suggested a resorptive process (Fig. 1b3). A well-developed GBM reaction surrounded the deposits with overlying foot process effacement. These findings also indicated type V LN.
The third biopsy at the age of 57 years revealed advanced glomerulosclerosis (5/25 glomeruli), and PAM silver staining exhibited a primarily bubbly appearance and dome patterns; the spikes had almost disappeared on LM examination (Fig. 1c1). Conversely, the IF findings showed a scattered distribution of the IgG deposits with negative C3 and C1q (Fig. 1c2). TEM also revealed a marked decrease in the electron density of the deposits that had been clearly seen in the previous two biopsies. Instead, GBM thickening and wrinkling were seen (Fig. 1c3). We doubted that the results of TEM and IF therefore differed from those of LM. Another remarkable finding on LM was arteriolar hyalinosis, which could be explained as arteriolopathy caused by calcineurin inhibitors. No evidence of calcineurin inhibitor toxicity such as striped interstitial fibrosis or tubular atrophy was observed. Tubular and interstitial lesions were attributed to the effect of renal sclerosis because of hypertension. The increase in urinary protein excretion could be explained by severe arterial sclerosis and calcineurin inhibitor-induced arteriolopathy rather than exacerbation of LN.
C4d is described as a byproduct of activation of the classical and lectin pathways. Because C4d acts as a positive marker for an immune complex-mediated mechanism in glomerular nephritis, C4d staining can be helpful in revealing immune complex deposition [11]. Unfortunately, we could not examine the C4d properties of the deposits using frozen sections because of a lack of additional tissue remaining in the block. Therefore, to confirm that LN was not the main cause of the clinical proteinuria, we investigated the GBM using a different method.
For further evaluation, we observed the GBM in all three biopsy specimens using LV-SEM (Hitachi Tabletop microscope TM4000; Hitachi High-Technologies Corp., Tokyo, Japan). In the first renal biopsy at the age of 48 years, LV-SEM of glomeruli retrieved from formalin-fixed paraffin-embedded tissue (PAM stain) revealed extensive and numerous subepithelial holes where deposits were thought to have been present. Additionally, well-developed GBM material formed spikes around the holes (Fig. 2a1). However, these holes were not found on the glomerular capillary luminal side (Fig. 2a2). This finding corresponded to Ehrenreich-Churg stage II membranous nephropathy (MN). The second renal biopsy at the age of 54 years showed a well-developed GBM reaction surrounding the holes where deposits might have been present; this finding was equivalent to Ehrenreich-Churg stage III MN (Fig. 2b1). Epithelium had formed and covered holes found in the first renal biopsy tissue, and it was difficult to see holes when looking down from the subepithelial side (Fig. 2b1). The GBM of the glomerular capillary lumina was almost covered by basement membrane material, and holes were still only partially open (Fig. 2b2). The third renal biopsy at the age of 57 years exhibited epithelium covered by newly formed GBM material, with openings in the GBM inward toward the glomerular capillary lumen (Fig. 2c1, c2). We speculated that the holes in the glomerular capillary luminal side might emerge when immune complex deposits in the GBM wash out.
In studying the third renal biopsy specimen, we also drew a comparison between the IF findings of the scattered distribution of the deposits and the LV-SEM findings. We stained frozen sections for IF with PAM and examined them with LV-SEM. We compared and observed the same glomeruli (Fig. 3). No IgG staining was confirmed using IF, which suggested that no deposits were present in the GBM (Fig. 3a). However, many cavities were confirmed using LV-SEM (FIG. 3b). Therefore, it was considered that no deposit was present in the many holes, and it was presumed that washout of the immune complex deposits occurred in the membranous LN. Overall, further observation of the GBM with LV-SEM confirmed resolution of class V LN. This case was similar to stage IV MN according to the Ehrenreich-Churg staging criteria.
A case report by Nonaka et al. [12] described the conventional TEM assessment of subepithelial deposits in a patient with mild membranous LN. However, few cases of LN evaluated using LV-SEM in which the loss of immune complex deposits was discovered have been reported. Clinicians emphasize IgG deposition in the diagnosis of LN. Many clinicians tend to consider that LN is highly unlikely if IgG is negative using IF examination. In the present case, however, the diagnosis of LN was confirmed in the first and second renal biopsies.
This is our first experience of a case in which the pathological findings were presumed to indicate a state of resolution of class V LN, and we thought that this was a highly contradictory finding. We had doubts regarding whether the histopathological findings of LN disappear (as in common MN) as the disease activity of SLE decreases.
Discussion/Conclusion
In the present study, we found that membranous LN diminished or resolved over the course of the three renal biopsies. To help clarify this process, we evaluated the patient's kidney biopsy tissue using LV-SEM, which allows for observation of both sides of the GBM. By studying the three-dimensional structure of the GBM using LV-SEM, we confirmed the formation of holes on the glomerular capillary luminal side. From these findings, we suspected that the same pathology of the membrane washout phenomenon that occurs in MN occurred in our patient with LN.
LV-SEM sometimes outperforms the conventional technique, TEM. TEM is the superior technique for investigating cross-sectional images of various components in glomeruli; however, performing three-dimensional and whole/wide observations using ultrathin sections is difficult because of the limitation of the observable size. LV-SEM can be used to evaluate the three-dimensional ultrastructural changes of the glomerular extracellular matrices in the same specimen used for LM. It thus provides more detailed three-dimensional information [8, 9]. Therefore, to review the morphological alterations of the glomeruli in a three-dimensional, broad area, we examined the LM slides of the renal biopsy specimens using LV-SEM.
LV-SEM examination of the first biopsy revealed many openings or holes in the subepithelium, consistent with the LM, IF, and TEM findings. The second renal biopsy showed a well-developed GBM reaction surrounding the openings or holes with overlying foot process effacement. These LV-SEM results were almost identical to those of TEM. The third renal biopsy showed openings on the thickened GBM inward toward the glomerular capillary lumina and loss of the electron density of the deposits in TEM. We confirmed the findings of some openings or holes in the GBM on the luminal side of the vessel using LV-SEM. Thus, we suspected that the deposits were washed out through these holes. In other words, the findings we confirmed using LV-SEM might result from washout of the immune complexes (only the cavity remained after washout). This concept allows for the possibility of finding IgG positivity on IF, which can be said to be an essential marker of LN. IgG was negative using IF in the tissue from the third renal biopsy in this patient.
Furthermore, it is possible that LV-SEM might be useful for monitoring disease, in contrast to interpreting potentially challenging serological results. An example is M-type phospholipase A2 receptor (PLA2R)-negative MN. PLA2R-negative secondary MN is generally characterized by the irregular distribution and size of subepithelial deposits and the presence of irregular subendothelial and mesangial deposits in glomeruli. We believe that there may be some difference in the GBM of PRA2R-positive or -negative MN evaluated in detail using LV-SEM.
The Ehrenreich-Churg classification divides MN into four pathological stages according to the state of immune complex deposition and change in the GBM [13]. Stage IV MN is characterized by loss of the electron density of the deposits, transition to a “washout” state, and development of electron-lucent zones within an irregularly thickened GBM [13]. Furthermore, the GBM recovers to an almost normal morphology in stage V MN [14]. The GBM returns to its normal form without deposition or thickening in the state of washed-out MN. In the present case, however, LM did not show findings consistent with normalization of the GBM morphology, similar to the washout image seen in stage IV or V MN, and changes such as thickening and spike formation persisted. However, IgG and C3 deposits cannot be seen using IF staining. TEM also exhibited few deposits. This series of pathophysiological findings has been confirmed by observations on resolving glomerulopathy in serial allograft biopsies [15].
Based on these results, we postulated a pathological process beginning with LN that caused deposition of immune complexes on the GBM. A decrease in LN activity then led to loss of these deposits as the disease progressed to a state of stage V MN washout, which results in a bubbly appearance. That is, despite resolution of LN, LM showed a remarkable change in the GBM. When LM shows noticeable changes in the GBM and specific clinical findings are present (excessive urinary protein), clinicians will usually think that the cause is LN.
The opening on the GBM is normally covered by vascular endothelium. However, in MN, complement complexes might injure the GBM by inducing the production of reactive oxygen species, thus altering the membrane structure [16]. At that time, a large proportion of the immune complex might have passed through the GBM from the glomerular capillary luminal side toward the epithelial side and nephrosis developed. We suspected that in the present case, this backward event (from the epithelial side toward the glomerular capillary luminal side) could have occurred during the LN washout phase. In other words, we suspected the possibility that these holes observed on the glomerular capillary luminal side were formed when the immune complexes were washed out.
In conclusion, our patient exhibited a loss of LN activity and a change to a state of resolution of class V LN. Renal biopsy revealed negative conversion of IgG on IF, and spikes and domes were present in the GBM on LM. We believe that the evaluation of three-dimensional structural alterations in GBM using LV-SEM might be a useful approach for assessing variation in renal biopsies over time.
Statement of Ethics
This study was conducted according to the guidelines laid down in the World Medical Association Declaration of Helsinki. Informed consent was obtained from the patient described in this case report, and the consent allowed their data to be stored, as required by the Hiroshima University Hospital. Written consent to publish this information was obtained from the patient (images and publication).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not funded by any third party.
Author Contributions
M.Y., S.H., and T.D. contributed to the data collection. S.H. and T.M. designed the research. Y.M. and A.S. evaluated the pathological tissue. M.Y. and S.H. performed the primary manuscript preparation. M.Y., S.H., T.D., and T.M. wrote the paper. T.M. has primary responsibility for the final content. M.Y., S.H., T.D., Y.M., and A.S. reviewed the paper and revised it critically. All authors read and approved the final manuscript.
Acknowledgments
We thank Angela Morben, DVM, ELS, and Andrea Baird, MD, from Edanz Group (https://en-author-services.edanzgroup.com/), for editing drafts of the manuscript.
Fig. 1 Renal biopsy findings. a First renal biopsy. a1 LM revealed that the basement membrane was thickened and exhibited mainly spikes (red arrowheads) (PAM stain). Scale bar, 25 μm. a2 IF staining demonstrated coarsely granular deposits of IgG, C3, and C1q in the capillary walls (IF microscopy, IgG, C3, C1q; ×200). a3 TEM showed abundant subepithelial deposits. The pattern was equivalent to Ehrenreich-Churg stage II MN. Scale bar, 2 µm (TEM). b Second renal biopsy. b1 The basement membrane showed a global increase in thickening and a bubbly appearance on LM (red arrowheads). This appearance was comparable with Ehrenreich-Churg stage III MN (PAM stain). Scale bar, 50 μm. b2 IF exhibited coarsely granular deposits of IgG, C3, and C1q in the capillary basement membrane, as in the previous examination (IF microscopy, IgG, C3, C1q; ×200). b3 TEM examination showed that the dense deposits were smaller and had been partly resorbed. A well-developed basement membrane reaction surrounded the deposits with overlying foot process effacement. Scale bar, 2 µm (TEM). c Third renal biopsy. c1 The basement membrane was thickened and exhibited a general meandering-like wrinkling pattern as seen on LM. The bubbly appearance was the same as in the second biopsies (PAM stain). Scale bar, 50 μm. c2 IF showed almost negative conversion of IgG and negative C3 and C1q (IF microscopy, IgG, C3, C1q; ×200). c3 On TEM, the basement membrane showed global thickening, wrinkling, and podocyte foot process effacement. The electron density of the deposits was unclear. Scale bar, 2 µm (TEM). C, complement; IF, immunofluorescence; IgG, immunoglobulin G; LM, light microscopy; MN, membranous nephropathy; PAM, periodic acid methenamine silver; TEM, transmission electron microscopy.
Fig. 2 Renal biopsy findings using LV-SEM. a First renal biopsy. a1 An image from the epithelial side of the GBM. Basement membrane material accumulated between many holes (deposit-like appearance) and projected into the urinary space as “spikes” (red arrowheads). The holes were not covered with basement membrane. Scale bar, 2.5 μm. a2 An image from the glomerular capillary lumina. The GBM of the glomerular capillary luminal side was covered by the material of the basement membrane, and no opening was seen (blue arrowheads). Scale bar, 2.5 μm. b Second renal biopsy. b1 An image from the epithelial side of the GBM. Intramembranous holes were observed. These holes (deposit-like appearance) were surrounded by well-developed basement membrane material (red arrowheads). In the subepithelium of the GBM, basement membrane material was newly formed on the holes, and the holes seen in a1 could not be confirmed from the epithelium side view. Scale bar, 5 μm. b2 An image from the glomerular capillary lumina. The GBM of the glomerular capillary lumina was almost covered by basement membrane material, and holes were still only partially open. Scale bar, 2.5 μm. c Third renal biopsy. c1 An image from the epithelial side of the GBM. Thickening of the basement membrane was still present. Vacuolation was present in potential spaces where the deposits might have been. The holes on the epithelium side shown in a1 were hardly observed. Scale bar, 2.5 μm. c2 An image from the glomerular capillary lumina. In contrast to c1, openings were present on the glomerular basement membrane inward toward the glomerular capillary lumina (blue arrowheads). Electron-lucent-like areas probably represented resorption of prior subepithelial immune complexes. Scale bar, 5 μm. GBM, glomerular basement membrane; LV-SEM, low-vacuum scanning electron microscopy.
Fig. 3 Comparison between IF microscopy and LV-SEM findings. a PAM stain of an IF-stained specimen. IF staining seemed to be almost nonexistent (red arrowhead and circle). b LV-SEM findings did not clearly confirm the immune complex deposition in the area (red arrowhead and circle). Examination of the site with LV-SEM indicated washout of the immune complex deposition. IF, immunofluorescence; LV-SEM, low-vacuum scanning electron microscopy; PAM, periodic acid methenamine silver.
Table 1 Patient's laboratory results upon admission at the age of 57 years
Parameter Value Reference range
Urine
pH 5.5 5.0–6.5
Red blood cells, /HPF 0–1 <5
Fatty casts, /WF 1–4 Negative
Epithelial casts, /WF 1–4 Negative
Urine protein/creatinine ratio, g/g 2.68 <0.15
N-acetyl-β-D-glucosaminidase, IU/L 13.2 0.7–11.2
β2-Microglobulin, µg/L 0.75 <230
Blood
Leukocyte count, /µL 4,750 4,500–9,000
Lymphocytes, /µL 940 1,200–3,690
Hemoglobin, g/dL 11.9 13.6–17.0
Platelet count, ×104/µL 20.7 14–36
Urea nitrogen, mg/dL 21.4 8.0–22.0
Creatinine, mg/dL 0.85 0.60–1.10
Estimated GFR, mL/min/1.73 m2 53 >90
Uric acid, mg/dL 6.0 3.6–7.0
Total protein, g/dL 6.2 6.7–8.3
Albumin, g/dL 3.7 4.0–5.0
Sodium, mEq/L 140 138–146
Potassium, mEq/L 5.3 3.6–4.9
Chloride, mEq/L 108 99–109
Corrected serum calcium, mg/dL 8.8 8.6–10.4
Phosphate, mg/dL 3.5 2.5–4.7
C-reactive protein, mg/dL 0.07 <0.30
CH50, CH50/mL 48.7 25–48
C3, mg/dL 98 65–135
C4, mg/dL 26 13–35
IgG, mg/dL 630 870–1,700
IgA, mg/dL 170 110–410
IgM, mg/dL 18 33–190
Anti-nuclear antibody ×320 <×40
(staining patterns) homologous, speckled
Anti-ssDNA antibody, IU/mL 2.8 <2.0
Anti-dsDNA antibody, IU/mL 5.8 <2.0
CH50, 50% hemolytic complement; dsDNA, double-stranded DNA; GFR, glomerular filtration rate; HPF, high-power field; Ig, immunoglobulin; ssDNA, single-stranded DNA; WF, whole field. | Oral | DrugAdministrationRoute | CC BY-NC | 33708798 | 19,404,881 | 2021 |
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