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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lung infiltration'. | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | CLOZAPINE | DrugsGivenReaction | CC BY-NC-ND | 33591960 | 18,991,249 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Overdose'. | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | CLOZAPINE | DrugsGivenReaction | CC BY-NC-ND | 33591960 | 18,991,545 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumomediastinum'. | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | CLOZAPINE | DrugsGivenReaction | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia'. | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | CLOZAPINE | DrugsGivenReaction | CC BY-NC-ND | 33591960 | 18,991,545 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory failure'. | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | CLOZAPINE | DrugsGivenReaction | CC BY-NC-ND | 33591960 | 18,991,545 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rhabdomyolysis'. | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | CLOZAPINE | DrugsGivenReaction | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sepsis'. | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | CLOZAPINE | DrugsGivenReaction | CC BY-NC-ND | 33591960 | 18,991,249 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Septic shock'. | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | CLOZAPINE | DrugsGivenReaction | CC BY-NC-ND | 33591960 | 18,991,249 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sinus tachycardia'. | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | CLOZAPINE | DrugsGivenReaction | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Somnolence'. | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | CLOZAPINE | DrugsGivenReaction | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | CLOZAPINE | DrugsGivenReaction | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
What was the administration route of drug 'CLOZAPINE'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
What was the outcome of reaction 'Anticholinergic syndrome'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
What was the outcome of reaction 'Coma scale abnormal'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Not recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,991,249 | 2021-02-16 |
What was the outcome of reaction 'Crush syndrome'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
What was the outcome of reaction 'Disturbance in attention'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
What was the outcome of reaction 'Emphysema'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
What was the outcome of reaction 'Hypertension'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
What was the outcome of reaction 'Intentional overdose'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 19,041,521 | 2021-02-16 |
What was the outcome of reaction 'Overdose'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,991,545 | 2021-02-16 |
What was the outcome of reaction 'Pneumomediastinum'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
What was the outcome of reaction 'Pneumonia'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,991,545 | 2021-02-16 |
What was the outcome of reaction 'Respiratory failure'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,991,545 | 2021-02-16 |
What was the outcome of reaction 'Septic shock'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,991,545 | 2021-02-16 |
What was the outcome of reaction 'Sinus tachycardia'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
What was the outcome of reaction 'Somnolence'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,986,056 | 2021-02-16 |
What was the outcome of reaction 'Toxicity to various agents'? | Successful Treatment of an Acute High-Dose Clozapine Poisoning without Detoxication.
BACKGROUND Clozapine is a well-proven atypical antipsychotic drug used for therapy of treatment-resistant schizophrenia. Over the last decades only a few cases of clozapine poisoning have been reported. Hence, guidelines for in-hospital management are currently not available. Most of the reported cases underwent detoxication measures as charcoal therapy and/or gastric lavage. However, there is no evidence for primary detoxication to improve clinical outcome. In contrast, use of therapy with intravenous physostigmine in the case of anticholinergic syndrome is restricted due to concerns about safety and dosing. We present a case of acute high-dose clozapine poisoning without detoxication and complete recovery supported by physostigmine. CASE REPORT We report the case of a 28-year-old man with prior diagnosed schizophrenia who presumably ingested 8 g (regular maximum daily dose 900 mg/d) of clozapine with uncertain intent. Initial computed tomography (CT) showed pulmonary infiltrates and widespread pneumomediastinum and soft-tissue emphysema of unknown genesis. The patient developed a progressive impairment of vigilance and respiratory insufficiency requiring invasive artificial ventilation for 31 h. Afterwards, an anticholinergic syndrome led again to impaired vigilance, tachycardia, and hyperventilation. To avoid risks associated with artificial ventilation, we applied physostigmine. Subsequently, the anticholinergic syndrome and the pneumomediastinum completely regressed and no further artificial ventilation was needed. CONCLUSIONS Based on the presumably ingested dosage, we present the likely highest reported nonfatal overdose of clozapine without detoxication. Additionally, we observed widespread pneumomediastinum as an uncommon complication. Our approach was to refrain from detoxication to minimize complications and to treat early with physostigmine because of anticholinergic syndrome to minimize its impact and to avoid artificial ventilation due do vigilance impairment.
Background
Clozapine is an established atypical antipsychotic drug used for treatment of schizophrenia. In contrast to conventional neuroleptics, it rarely provokes extrapyramidal adverse effects. Several poisoning-associated symptoms like impaired vigilance, agitation, tachycardia, renal failure, and pulmonary complications such as aspiration pneumonia have been reported [1–3]. Few (and mostly nonfatal) cases of clozapine poisoning have been reported that included detoxication as a management option [1–6]. As clozapine poisoning is uncommon, guidelines for in-hospital management are not available.
We present an acute clozapine poisoning case, with likely the highest reported dose (presumably 8 g) and survival without detoxication.
Case Report
A 28-year-old man with schizophrenia and suspected high-dose clozapine poisoning was admitted to our Emergency Department. The patient had a legal guardian with whom he usually had daily contact. The guardian alerted the police because he could not reach the patient any more. Before admission, the patient was found in his apartment with impaired vigilance of unknown duration without evidence of physical trauma. The emergency medical service found 8 depleted blisters of clozapine (10 tablets per blister, 100 mg/tablet, total 8 g) next to him, presumably ingested, with unclear intent. There were no signs of preceding emesis.
At initial clinical examination, the patient was somnolent with reduced Glasgow coma scale of 11 points, sinus tachycardia (130/min), and hypertension (157/93 mmHg). After consultation with the central emergency poisoning center, a watch and wait strategy including symptomatic therapy was recommended. Cranial computed tomography (CT) was performed without detection of cerebral pathologies. Thoracic CT showed pulmonary infiltrates and atelectasis on both sides. As an incidental finding, a widespread pneumomediastinum and soft-tissue emphysema of unknown genesis was diagnosed (Figure 1).
Laboratory findings revealed rhabdomyolysis and a crush syndrome with acute renal failure AKIN II (creatinine=188 µmol/l, myoglobin=6231 µg/l, creatine kinase=367 µkat/l), possibly triggered by the clozapine poisoning. Urine investigations showed no evidence of other drugs.
During the initial hours in the Emergency Department, the patient developed a progressive impairment of vigilance and respiratory insufficiency (GCS=7, peripheral oxygen saturation via pulse oximeter < 90% despite oxygen insufflation via nasal cannula and respiratory rate of 26 per minute) requiring invasive ventilation. The patient initially had no fever. Bronchoscopy and esophagogastroduodenoscopy remained without evidence of an anatomical air leakage.
Based on the initial SOFA score of 15 points, sepsis caused by a community-acquired bilateral pneumonia was diagnosed and treated with Piperacillin/Tazobactam according to the guidelines for management of sepsis.
Approximately 10 h after hospital admission, the patient was admitted to our Intensive Care Unit (ICU). Upon arrival at the ICU, the patient was found to be in septic shock, requiring vasopressors. However, vasopressors could be tapered after sufficient fluid supplementation. Subsequently, the patient became hypertensive and developed moderate tachycardia. Therefore, sodium nitroprusside was required.
After successful respiratory, weaning the patient was extubated after 31 h of invasive ventilation and respiration remained stayed thereafter. The subsequent period of drowsiness (Richmond Agitation-Sedation Scale-2), tachycardia, hypertension, inadequate communication, and hyposalivation was interpreted as an anticholinergic syndrome and treated by intravenous physostigmine. Afterwards, the patient became more awake (Richmond Agitation-Sedation Scale 0), and his tachycardia and hypertension resolved.
The therapy with physostigmine was guided by vital signs and clinical symptoms (drowsiness, salivation, and sweating) and was stopped after a cumulative administration of 21 mg and 2 days of treatment.
At day 6 of hospitalization, a follow-up CT was performed. The pneumomediastinum and soft-tissue emphysema were completely regressed. The pneumonia was clinical and para-clinical in healing process (Figure 2).
Retrospective serum clozapine analysis revealed the clozapine level had decreased from toxic to therapeutic at day 4 (Figure 3).
After consultation with our psychiatrists on day 6 after poisoning, the patient was directly transferred to the Psychiatry Department. The patient confirmed the clozapine intake without a clear statement concerning the doses, but he denied a suicidal intention.
At the day of transfer, the patient was completely awake (Richmond Agitation-Sedation Scale 0) and oriented, in good general and respiratory condition, without need for oxygen supply. Laboratory findings showed a regression of renal failure, rhabdomyolysis and inflammation (creatinine=78 µmol/l, myoglobin=145 µg/l, white blood count=10.5 GPt/l).
Discussion
In recent decades only a few and mostly nonfatal cases of clozapine poisoning have been reported, all including detoxification measures [1–6]. Different factors may be responsible for this low incidence. A leading cause may be the restricted and supervised use of the drug [4]. Clozapine is not a first-line therapy, but is reserved for treatment-resistant schizophrenia. Furthermore, weekly laboratory examinations are recommended, especially at the beginning of therapy, to exclude agranulocytosis [7]. This supervision helps maintain patient medication compliance, particularly in case of adverse effects. Most adverse effects disappear during the initial 4–6 weeks of treatment due to the development of tolerance [8,9]. Based on this clinical experience, some authors postulate greater toxicity in patients with acute clozapine poisoning who have not been exposed to it previously [4,10]. The evidence and pathophysiology of this hypothesis remain uncertain.
As clozapine poisoning is uncommon, guidelines for in-hospital management are not available. Therefore, our therapy was based on an evidence-based consensus guideline for out-of-hospital management as well as several position papers published by the European Association of Poison Centers and Clinical Toxicologists and the American Academy of Clinical Toxicology [11–14].
Specific antidotes for clozapine are not available. In general, treatment measures are mostly limited to symptomatic therapy such as monitoring, airway management, and intravenous fluids in case of hypotension [14]. In previous case reports, detoxication with activated charcoal therapy and gastric lavage were performed and recommended [1,3,4,15]. These treatment measures need to be discussed critically. Firstly, there is no evidence that primary detoxication by charcoal therapy and gastric lavage improves clinical outcome [11,12,14]. Secondly, especially in clozapine poisoning, depressed levels of consciousness are common, so charcoal therapy and gastric lavage are contraindicated in case of unprotected airways [11,12]. Thirdly, secondary detoxication measures such as forced diuresis and renal replacement therapy are ineffective because of the mostly hepatic metabolism of clozapine [15].
Based on this knowledge, we decided against performing established primary and secondary detoxication. In addition, unlike previously reported complications, our patient suffered a widespread pneumomediastinum of unknown genesis. Retrospectively, it was most likely caused by emesis. This circumstance supports our restrictive management regarding detoxication.
To date, the highest reported oral intake of clozapine was 16 g [4] and the highest reported serum peak level was 9100 ng/ml [3]. Both cases were nonfatal and treated with activated charcoal therapy and/or gastric lavage. Based on the presumably ingested dosage (8 g), our case is the likely highest reported nonfatal overdose of clozapine without applying detoxication measures but with complete recovery of the poisoning-associated effects of pneumonia, rhabdomyolysis, and anticholinergic syndrome.
Rhabdomyolysis is known to be caused by different drug intoxications and has been also reported in clozapine overdose, as indicated by elevated creatinine kinase levels [16]. Usually, causal associations between drugs and adverse events are based on clinical judgement [17]. To enable a more objective assessment of adverse drug reactions, Naranjo et al designed a probability scale [17]. According to this, rhabdomyolysis in our patient was possibly (4 points) related to clozapine [17]. However, in our case, immobilization and infection may also be contributing factors for the development of rhabdomyolysis. Considering these causes, our treatment focused on discontinuation of clozapine and administration of anti-infective therapy supported by fluid supplementation.
Another serious complication following clozapine poisoning is anticholinergic syndrome. The pharmacological property of clozapine provides antipsychotic effects mainly by inhibition of dopamine D4-receptors [18]. In contrast, lower affinity to D2 and other dopamine receptors minimizes the incidence of extrapyramidal adverse effects [18]. However, due to inhibition of muscarinic receptor M1, clozapine may induce anticholinergic adverse effects which may aggravate to an anticholinergic syndrome [18,19]. Several studies supported cholinesterase inhibitors for treatment of anticholinergic syndrome [19–22]. However, only physostigmine can cross the blood-brain barrier and thereby antagonize central as well as peripheral anticholinergic effects [23]. Nevertheless, its use is limited due to concerns about safety and dosing, although most adverse effects are avoidable by conservative dosing strategies [19].
In our patient, we detected peripheral and central nervous system symptoms like mydriasis, tachycardia, and delirium. As the non-pharmacological delirium therapy remained ineffective, we decided to apply physostigmine for diagnostic as well as therapeutic reasons. Within several minutes, the patient showed improved vigilance and thereby confirmed our diagnosis of an anticholinergic delirium. However, physostig-mine has a rapid plasma elimination, which resulted in recurrence of depressed consciousness. To avoid the need for invasive airway management, we continued the therapy with physostigmine, leading to complete physical recovery without adverse effects.
Conclusions
The present case suggests that relying on a symptomatic therapy without detoxication, even in cases of an acute high-dosage clozapine poisoning, can be sufficient.
In patients with refractory delirium and peripheral anticholinergic signs (eg, mydriasis, hyposalivation, dry skin) with suspected anticholinergic syndrome, we tend to recommend early treatment with physostigmine as a diagnostic and therapeutic approach. Physostigmine may shorten the time to recovery and lower the incidence of complications compared to invasive airway management. Drug administration should be monitored by ECG and antagonized by atropine in case of adverse effects (eg, bradycardiac arrhythmias).
Physicians should also be vigilant for uncommon complications such as a pneumomediastinum that might be caused by unprovoked emesis.
Conflict of Interest
None
Figure 1. Thoracic CT at day 1: Pneumomediastinum and soft-tissue emphysema.
Figure 2. Thoracic CT at day 6: Pneumomediastinum and soft-tissue emphysema completely regressed.
Figure 3. Serum levels of clozapine and major metabolite norclozapine at days 1, 4, and 7 after poisoning. | Recovered | ReactionOutcome | CC BY-NC-ND | 33591960 | 18,991,545 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperammonaemic encephalopathy'. | Sunitinib-associated hyperammonemic encephalopathy successfully managed with higher intensity conventional hemodialysis: A case report.
BACKGROUND
Hyperammonemia encephalopathy is a rare but severe complication that has been reported in association with the use of sunitinib, a tyrosine kinase inhibitor. We report here a unique case of a patient with end stage renal disease that was initiated on sunitinib for metastatic renal cell carcinoma.
A 65-year-old man with end stage renal disease on maintenance conventional hemodialysis and had concomitant stable Child-Pugh class B liver cirrhosis consequent of hepatitis C infection was started on sunitinib for metastatic renal cell carcinoma. He developed confusion few weeks after starting therapy with no other indication of worsening liver dysfunction otherwise.
METHODS
He was later diagnosed with hyperammonemia encephalopathy.
METHODS
His treatment was discontinued and reinitiated at a lower dose after recovery and titrated according to tolerance. As ammonia is a very low molecular weight molecule and is cleared well with diffusive clearance, we intensified his dialysis regimen by increasing intensity for each session and frequency per week.
RESULTS
With this change in dialysis regimen, patient was able to continue treatment with sunitinib.
CONCLUSIONS
Clinicians prescribing sunitinib should be vigilant to monitor for this complication in patients receiving sunitinib, apart from the more usual presentation of hepatotoxicity. We found that a more intensive hemodialysis regimen consisting of 4× a week conventional high-flux hemodialysis (HD) can permit the continuation of treatment with sunitinib in an end stage renal disease (ESRD) patient with Child-Pugh class B liver cirrhosis.
1 Introduction
The incidence of renal cell carcinoma (RCC) in end stage renal disease (ESRD) population is many-fold higher than that of the general population, especially those with acquired cystic kidney disease associated with ESRD.[1] A proportion of these are diagnosed with advanced stage metastatic RCC at the onset. Approximately 80% of RCC is of the clear cell type and with better molecular understanding of the disease biology; various targeted therapies are available today for different disease stages that require systemic therapy beyond surgical excision. Metastatic RCC is difficult to treat and treatment options are usually toxic with poor response rate. The advent of tyrosine kinase inhibitor (TKI) as effective therapy for metastatic RCC resulted from discovery that disruption of the vascular endothelial growth factor (VEGF) signaling pathway can retard tumor growth and progress.[2] Sunitinib has inhibitory effect on many receptor kinases such as VEGF receptors and platelet derived growth factor (PDGF) receptors. It is one of the current recommended evidence-based systemic therapies for metastatic RCC.[3]
Sunitinib is approved for use in ESRD patients on hemodialysis (HD) with no initial dose adjustment needed.[4] Sunitinib and its metabolite is also highly protein bound (>90%) and hence, very little is removed during treatment with conventional (high-flux) HD. According to the prescribing information (provided by Food and Drug Administration), the pharmacokinetic of sunitinib is not different in stable patients with Child-Pugh class A and B liver cirrhosis.[4]
This purpose of this report to highlight the occurrence of a rare complication arising from the use of sunitinib and how it was managed given the unique situation that the patient was already established on maintenance HD.
The National Healthcare Group Institutional Review Board determined that case report does not meet definition of human-subject research and approval was not required. Written informed consent for patient information to be published was provided by patient.
2 Case report
A 65-year-old man who was on maintenance HD for 27 years presented with gross hematuria for which subsequent imaging was highly suggestive of renal malignancy. He underwent left radical nephrectomy as it was a local disease and pathology confirmed RCC. Two years after the nephrectomy, he was unfortunately diagnosed with metastatic RCC. His past history was significant for Child-Pugh class B hepatitis C (HCV) related liver cirrhosis (albumin 28–35 g/L, Bilirubin <34 μmol/L, INR <1.7, presence of small amount of ascites, one past episode of grade 2 encephalopathy). The only episode of hepatic encephalopathy occurred 15 months before the diagnosis of metastatic RCC and was managed successfully with lactulose; he was subsequently started on rifaximin and had remained well since with no recurrence of encephalopathy. After deliberation of the various approaches for treatment, his oncologist considered TKI to be the best treatment option and started him on sunitinib 25 mg daily.
Our patient was brought to the emergency department (ED) with confusion and bilateral asterixis 44 days after initiation of sunitinib (patient was maintained on 25 mg daily throughout this period). After appropriate investigations including computed tomography (CT) of the brain had ruled out other causes, he was managed as for metabolic encephalopathy (grade 2). His serum ammonia level was 170.5 μg/dL at presentation. His symptoms resolved 4 days later (with discontinuation of sunitinib). His serum ammonia was reduced to 48.7 μg/dL. He received the same dialysis schedule during his hospitalization and was discharged to continue with his usual HD regimen (3×/wk and 3.5 h/session).
He was later seen by his oncologist and was started at a lower dose of 12.5 mg sunitinib daily 2 weeks after his discharge, increasing to 25 mg daily 4 weeks after being stable on the lower dose with no complaints. He presented to ED again with similar presentation of confusion and asterixis 28 days later after the increase in dose. His serum ammonia level was significantly elevated again at 176.1 μg/dL pre-dialysis, declining to 68.2 μg/dL post-dialysis. He was dialyzed with a larger surface area high-flux filter (polysulfone 1.6 m2) using blood flow rate of 280 mL/min and dialysate flow rate of 500 mL/min for 4 hours. His body weight was 54.5 kg. His confusion improved significantly post dialysis and he recovered the following day. He was maintained on sunitinib 25 mg daily and discharged well with a schedule for more intensive dialysis (higher frequency 4×/wk and with better clearance achieved by increased blood flow, longer duration, and larger filter). He was successfully kept out of hospital with no recurrence of encephalopathy with that dialysis schedule. There were no adverse events and episodes of confusion.
Except for the elevation in serum ammonia level, there were no changes in coagulation profile, bilirubin, or liver enzymes during each of these 2 admissions for encephalopathy. There were also no other precipitating factors for hepatic encephalopathy that was evident in these admissions. He did not experience constipation and was compliant with lactulose and rifaximin. CT brain done during his admission did not reveal structural brain pathology. He does not consume alcohol and did not take traditional Chinese medicine. He was not given any medication that can inhibit CYP3A4. He was also not taking any therapeutic agent that has reported association with hyperammonemia. Patient was jointly managed by a multi-disciplinary team (Liver, Medical Oncology and Nephrology). All management decisions were discussed and made jointly by consensus.
3 Discussion
It has been reported that elevations in serum aminotransferase level were common as observed from clinical trials with sunitinib (39% vs 23% in the control arm). Grade 3–4 elevation (>5× the upper limit of normal) occurred in about 2% to 3% of the trial subjects; most reversed with temporary discontinuation and were able to reinitiate at lower doses.[5] Hyperammonemia encephalopathy (HE) is a somewhat distinct entity. Ammonia is a by-product of nitrogen metabolism in human biology. Ammonia is highly toxic to the nervous system and hence, must be prevented via various physiological mechanisms from reaching a level that causes toxicity. The liver is one critical organ for ammonia catabolism by converting it to urea via the urea cycle although other organs such as the muscle and kidneys also have an important role in ammonia homeostasis. Serum ammonia level is profoundly altered in liver failure resulting in hyperammonemia due to the deficient ammonia clearance by the diseased liver and to the development of portal collateral circulation that diverts portal blood with high ammonia content to the systemic blood stream.[6] Ammonia has the ability to cross the blood brain barrier. Hyperammonemia state causes central nervous system (CNS) toxicity by inducing astrocyte swelling resulting from accumulation of intracellular glutamine as a consequent of ammonia detoxification within the astrocytes.[7]
HE with the use of sunitinib is a unique condition where there is no other demonstrable cause of hyperammonemia; specifically there is no clinical evidence of new onset or worsening liver disease which is one of the major known etiologies of hyperammonemia. There have been 6 other reported cases of HE with the use of sunitinib in the literature to date.[8–12] This is the first reported in a patient with ESRD on maintenance HD. While the patient was known to have chronic liver cirrhosis associated with hepatitis C infection, his disease was in stable course and he has not had any episode of encephalopathy in the 16 months preceding the use of sunitinib. His metastatic disease did not involve the liver. None of the previously published cases had background of liver cirrhosis although some did have primary or metastatic disease involving the liver. Comparison of the cases (Table 1) revealed different doses of sunitinib exposure as well as number of days before patients manifest symptoms of HE. Most of the cases of HE reported with the use of sunitinib has onset of between 10 and 14 days. Our patient presented with HE 44 and 28 days after initiation of treatment with sunitinib. Although this may have been partly influenced by the dose of sunitinib used, we believe that this delayed manifestation was because the HD had protected the patient from high level of serum ammonia. He did present with HE eventually when his regular HD regimen was no longer able to cope with the generation of serum ammonia. The pathobiology behind this is uncertain. It is probably not related to urea cycle disorder as the patient recovered without the use of nitrogen scavenger or replacement of urea cycle intermediates.
Table 1 Summary of characteristics of previously reported cases of hyperammonemia encephalopathy associated with the use of sunitinib.
Case Tumor Liver condition and renal function Sunitinib dose/mg Days between drug initiation and encephalopathy Ammonia level, μmol/L Treatment Days to recovery
Our patient-1st admission RCC CirrhosisALT 20 U/LAST 27 U/LNormal bilirubinESRD on hemodialysis 25 44 122 Dialysis (usual)+ lactulose 3×/d+ Discontinuation of sunitinib 4
Our patient-2nd admission 25 28 126 Dialysis (increased intensity)+ lactulose 3×/d+Continuation of sunitinib 2
Lee et al[8] GIST (small bowel) Liver metastasesALT 50 U/LAST 79 U/LBilirubin not availableRenal function not available 50 14 150 Lactulose hourly+ Discontinuation of sunitinib 1
Lee et al[8] GIST (caecum) ALT 53 U/LAST 44 U/LBilirubin not availableRenal function not available 50 10 277 Lactulose hourly+ Discontinuation of sunitinib 1
Shea et al[9] PNET Liver metastasesALT 43 U/L, AST 53 U/LNormal bilirubinNormal renal function 12.5 14 147 Lactulose (ensure bowel opening 3×/d)+ Discontinuation of sunitinib 1
Pilanci et al[11] RCC ALT 25 U/LAST 34 U/LNormal bilirubinNo renal insufficiency 50 14 104 Lactulose hourly+ Discontinuation of sunitinib 7
Lipe et al[12] Infiltrating ductal carcinoma of breast with metastatis to liver Liver metastasisALT 54 U/LAST 100 U/LBilirubin not availableRenal function not available. Urinalysis normal No details 12 202 Lactulose (frequency not mentioned)+ Discontinuation of sunitinib 12
Hyperammonemia severe enough to cause encephalopathy has to be managed urgently. Lactulose is intensified and supplemented with an oral non-absorbable antibiotic rifaximin. Both these treatments work synergistically to reduce inhibit the growth of ammonia producing bacteria in the gastrointestinal tract.[13] Although reduction in ammonia load is certainly one important strategy, the removal of ammonia via HD is also very effective. Ammonia is not protein bound and much like urea, is a low-molecular-weight molecule (17 g/mol), hence clearance with HD is extremely effective and can reduce serum ammonia level by >50% after a single session (as evident in our case). Given the property of ammonia, the mode of clearance is not critical. Hemodiafiltration (HDF) has little advantage over high-efficiency HD in ammonia removal. Similar to urea clearance, increasing dialyzer (filter) size, blood flow, and dialysate flow will all enhanced the clearance of ammonia.[14] When the decision was made that TKI (sunitinib) was the better option for managing his disease condition, we increased his intensity of HD (both single session efficiency as well as frequency to avoid the 72 hours weekend interval) to permit continuation of sunitinib. Patient was able to maintain treatment with sunitinib for 3 additional months with the intensified dialysis regimen that kept his serum ammonia below 80 μg/dL. Unfortunately, he later developed various infective episodes and decision was made to manage him conservatively with best supportive care only.
This report highlight the fact that a rare but serious drug related complication associated with the use of sunitinib can be managed successfully with intensive outpatient hemodialysis without discontinuation of the medication in a patient who is already on maintenance HD. The limitation is this a single case report in 1 patient. Nevertheless, it provides insight on possible management option for continuation of sunitinib in the case of hyperammonaemia encephalopathy in a hemodialysis patient.
Author contributions
Conceptualization: Sabrina Haroon, Stephanie Ko, Titus Lau.
Visualization: Sabrina Haroon, Titus Lau.
Writing – original draft: Sabrina Haroon, Stephanie Ko.
Writing – review & editing: Sabrina Haroon, Stephanie Ko, Alvin Wong, Tan Poh Seng, Evan Lee, Titus Lau.
Abbreviations: CT = computed tomography, ED = emergency department, ESRD = end stage renal disease, HCV = hepatitis C, HD = hemodialysis, HE = hyperammonemia encephalopathy, PDGF = platelet derived growth factor, RCC = renal cell carcinoma, TKI = tyrosine kinase inhibitor, VEGF = vascular endothelial growth factor.
How to cite this article: Haroon S, Ko S, Wong A, Tan PS, Lee E, Lau T. Sunitinib-associated hyperammonemic encephalopathy successfully managed with higher intensity conventional hemodialysis: a case report. Medicine. 2021;100:5(e24313).
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | SUNITINIB MALATE | DrugsGivenReaction | CC BY | 33592876 | 19,002,656 | 2021-02-05 |
What was the outcome of reaction 'Hyperammonaemic encephalopathy'? | Sunitinib-associated hyperammonemic encephalopathy successfully managed with higher intensity conventional hemodialysis: A case report.
BACKGROUND
Hyperammonemia encephalopathy is a rare but severe complication that has been reported in association with the use of sunitinib, a tyrosine kinase inhibitor. We report here a unique case of a patient with end stage renal disease that was initiated on sunitinib for metastatic renal cell carcinoma.
A 65-year-old man with end stage renal disease on maintenance conventional hemodialysis and had concomitant stable Child-Pugh class B liver cirrhosis consequent of hepatitis C infection was started on sunitinib for metastatic renal cell carcinoma. He developed confusion few weeks after starting therapy with no other indication of worsening liver dysfunction otherwise.
METHODS
He was later diagnosed with hyperammonemia encephalopathy.
METHODS
His treatment was discontinued and reinitiated at a lower dose after recovery and titrated according to tolerance. As ammonia is a very low molecular weight molecule and is cleared well with diffusive clearance, we intensified his dialysis regimen by increasing intensity for each session and frequency per week.
RESULTS
With this change in dialysis regimen, patient was able to continue treatment with sunitinib.
CONCLUSIONS
Clinicians prescribing sunitinib should be vigilant to monitor for this complication in patients receiving sunitinib, apart from the more usual presentation of hepatotoxicity. We found that a more intensive hemodialysis regimen consisting of 4× a week conventional high-flux hemodialysis (HD) can permit the continuation of treatment with sunitinib in an end stage renal disease (ESRD) patient with Child-Pugh class B liver cirrhosis.
1 Introduction
The incidence of renal cell carcinoma (RCC) in end stage renal disease (ESRD) population is many-fold higher than that of the general population, especially those with acquired cystic kidney disease associated with ESRD.[1] A proportion of these are diagnosed with advanced stage metastatic RCC at the onset. Approximately 80% of RCC is of the clear cell type and with better molecular understanding of the disease biology; various targeted therapies are available today for different disease stages that require systemic therapy beyond surgical excision. Metastatic RCC is difficult to treat and treatment options are usually toxic with poor response rate. The advent of tyrosine kinase inhibitor (TKI) as effective therapy for metastatic RCC resulted from discovery that disruption of the vascular endothelial growth factor (VEGF) signaling pathway can retard tumor growth and progress.[2] Sunitinib has inhibitory effect on many receptor kinases such as VEGF receptors and platelet derived growth factor (PDGF) receptors. It is one of the current recommended evidence-based systemic therapies for metastatic RCC.[3]
Sunitinib is approved for use in ESRD patients on hemodialysis (HD) with no initial dose adjustment needed.[4] Sunitinib and its metabolite is also highly protein bound (>90%) and hence, very little is removed during treatment with conventional (high-flux) HD. According to the prescribing information (provided by Food and Drug Administration), the pharmacokinetic of sunitinib is not different in stable patients with Child-Pugh class A and B liver cirrhosis.[4]
This purpose of this report to highlight the occurrence of a rare complication arising from the use of sunitinib and how it was managed given the unique situation that the patient was already established on maintenance HD.
The National Healthcare Group Institutional Review Board determined that case report does not meet definition of human-subject research and approval was not required. Written informed consent for patient information to be published was provided by patient.
2 Case report
A 65-year-old man who was on maintenance HD for 27 years presented with gross hematuria for which subsequent imaging was highly suggestive of renal malignancy. He underwent left radical nephrectomy as it was a local disease and pathology confirmed RCC. Two years after the nephrectomy, he was unfortunately diagnosed with metastatic RCC. His past history was significant for Child-Pugh class B hepatitis C (HCV) related liver cirrhosis (albumin 28–35 g/L, Bilirubin <34 μmol/L, INR <1.7, presence of small amount of ascites, one past episode of grade 2 encephalopathy). The only episode of hepatic encephalopathy occurred 15 months before the diagnosis of metastatic RCC and was managed successfully with lactulose; he was subsequently started on rifaximin and had remained well since with no recurrence of encephalopathy. After deliberation of the various approaches for treatment, his oncologist considered TKI to be the best treatment option and started him on sunitinib 25 mg daily.
Our patient was brought to the emergency department (ED) with confusion and bilateral asterixis 44 days after initiation of sunitinib (patient was maintained on 25 mg daily throughout this period). After appropriate investigations including computed tomography (CT) of the brain had ruled out other causes, he was managed as for metabolic encephalopathy (grade 2). His serum ammonia level was 170.5 μg/dL at presentation. His symptoms resolved 4 days later (with discontinuation of sunitinib). His serum ammonia was reduced to 48.7 μg/dL. He received the same dialysis schedule during his hospitalization and was discharged to continue with his usual HD regimen (3×/wk and 3.5 h/session).
He was later seen by his oncologist and was started at a lower dose of 12.5 mg sunitinib daily 2 weeks after his discharge, increasing to 25 mg daily 4 weeks after being stable on the lower dose with no complaints. He presented to ED again with similar presentation of confusion and asterixis 28 days later after the increase in dose. His serum ammonia level was significantly elevated again at 176.1 μg/dL pre-dialysis, declining to 68.2 μg/dL post-dialysis. He was dialyzed with a larger surface area high-flux filter (polysulfone 1.6 m2) using blood flow rate of 280 mL/min and dialysate flow rate of 500 mL/min for 4 hours. His body weight was 54.5 kg. His confusion improved significantly post dialysis and he recovered the following day. He was maintained on sunitinib 25 mg daily and discharged well with a schedule for more intensive dialysis (higher frequency 4×/wk and with better clearance achieved by increased blood flow, longer duration, and larger filter). He was successfully kept out of hospital with no recurrence of encephalopathy with that dialysis schedule. There were no adverse events and episodes of confusion.
Except for the elevation in serum ammonia level, there were no changes in coagulation profile, bilirubin, or liver enzymes during each of these 2 admissions for encephalopathy. There were also no other precipitating factors for hepatic encephalopathy that was evident in these admissions. He did not experience constipation and was compliant with lactulose and rifaximin. CT brain done during his admission did not reveal structural brain pathology. He does not consume alcohol and did not take traditional Chinese medicine. He was not given any medication that can inhibit CYP3A4. He was also not taking any therapeutic agent that has reported association with hyperammonemia. Patient was jointly managed by a multi-disciplinary team (Liver, Medical Oncology and Nephrology). All management decisions were discussed and made jointly by consensus.
3 Discussion
It has been reported that elevations in serum aminotransferase level were common as observed from clinical trials with sunitinib (39% vs 23% in the control arm). Grade 3–4 elevation (>5× the upper limit of normal) occurred in about 2% to 3% of the trial subjects; most reversed with temporary discontinuation and were able to reinitiate at lower doses.[5] Hyperammonemia encephalopathy (HE) is a somewhat distinct entity. Ammonia is a by-product of nitrogen metabolism in human biology. Ammonia is highly toxic to the nervous system and hence, must be prevented via various physiological mechanisms from reaching a level that causes toxicity. The liver is one critical organ for ammonia catabolism by converting it to urea via the urea cycle although other organs such as the muscle and kidneys also have an important role in ammonia homeostasis. Serum ammonia level is profoundly altered in liver failure resulting in hyperammonemia due to the deficient ammonia clearance by the diseased liver and to the development of portal collateral circulation that diverts portal blood with high ammonia content to the systemic blood stream.[6] Ammonia has the ability to cross the blood brain barrier. Hyperammonemia state causes central nervous system (CNS) toxicity by inducing astrocyte swelling resulting from accumulation of intracellular glutamine as a consequent of ammonia detoxification within the astrocytes.[7]
HE with the use of sunitinib is a unique condition where there is no other demonstrable cause of hyperammonemia; specifically there is no clinical evidence of new onset or worsening liver disease which is one of the major known etiologies of hyperammonemia. There have been 6 other reported cases of HE with the use of sunitinib in the literature to date.[8–12] This is the first reported in a patient with ESRD on maintenance HD. While the patient was known to have chronic liver cirrhosis associated with hepatitis C infection, his disease was in stable course and he has not had any episode of encephalopathy in the 16 months preceding the use of sunitinib. His metastatic disease did not involve the liver. None of the previously published cases had background of liver cirrhosis although some did have primary or metastatic disease involving the liver. Comparison of the cases (Table 1) revealed different doses of sunitinib exposure as well as number of days before patients manifest symptoms of HE. Most of the cases of HE reported with the use of sunitinib has onset of between 10 and 14 days. Our patient presented with HE 44 and 28 days after initiation of treatment with sunitinib. Although this may have been partly influenced by the dose of sunitinib used, we believe that this delayed manifestation was because the HD had protected the patient from high level of serum ammonia. He did present with HE eventually when his regular HD regimen was no longer able to cope with the generation of serum ammonia. The pathobiology behind this is uncertain. It is probably not related to urea cycle disorder as the patient recovered without the use of nitrogen scavenger or replacement of urea cycle intermediates.
Table 1 Summary of characteristics of previously reported cases of hyperammonemia encephalopathy associated with the use of sunitinib.
Case Tumor Liver condition and renal function Sunitinib dose/mg Days between drug initiation and encephalopathy Ammonia level, μmol/L Treatment Days to recovery
Our patient-1st admission RCC CirrhosisALT 20 U/LAST 27 U/LNormal bilirubinESRD on hemodialysis 25 44 122 Dialysis (usual)+ lactulose 3×/d+ Discontinuation of sunitinib 4
Our patient-2nd admission 25 28 126 Dialysis (increased intensity)+ lactulose 3×/d+Continuation of sunitinib 2
Lee et al[8] GIST (small bowel) Liver metastasesALT 50 U/LAST 79 U/LBilirubin not availableRenal function not available 50 14 150 Lactulose hourly+ Discontinuation of sunitinib 1
Lee et al[8] GIST (caecum) ALT 53 U/LAST 44 U/LBilirubin not availableRenal function not available 50 10 277 Lactulose hourly+ Discontinuation of sunitinib 1
Shea et al[9] PNET Liver metastasesALT 43 U/L, AST 53 U/LNormal bilirubinNormal renal function 12.5 14 147 Lactulose (ensure bowel opening 3×/d)+ Discontinuation of sunitinib 1
Pilanci et al[11] RCC ALT 25 U/LAST 34 U/LNormal bilirubinNo renal insufficiency 50 14 104 Lactulose hourly+ Discontinuation of sunitinib 7
Lipe et al[12] Infiltrating ductal carcinoma of breast with metastatis to liver Liver metastasisALT 54 U/LAST 100 U/LBilirubin not availableRenal function not available. Urinalysis normal No details 12 202 Lactulose (frequency not mentioned)+ Discontinuation of sunitinib 12
Hyperammonemia severe enough to cause encephalopathy has to be managed urgently. Lactulose is intensified and supplemented with an oral non-absorbable antibiotic rifaximin. Both these treatments work synergistically to reduce inhibit the growth of ammonia producing bacteria in the gastrointestinal tract.[13] Although reduction in ammonia load is certainly one important strategy, the removal of ammonia via HD is also very effective. Ammonia is not protein bound and much like urea, is a low-molecular-weight molecule (17 g/mol), hence clearance with HD is extremely effective and can reduce serum ammonia level by >50% after a single session (as evident in our case). Given the property of ammonia, the mode of clearance is not critical. Hemodiafiltration (HDF) has little advantage over high-efficiency HD in ammonia removal. Similar to urea clearance, increasing dialyzer (filter) size, blood flow, and dialysate flow will all enhanced the clearance of ammonia.[14] When the decision was made that TKI (sunitinib) was the better option for managing his disease condition, we increased his intensity of HD (both single session efficiency as well as frequency to avoid the 72 hours weekend interval) to permit continuation of sunitinib. Patient was able to maintain treatment with sunitinib for 3 additional months with the intensified dialysis regimen that kept his serum ammonia below 80 μg/dL. Unfortunately, he later developed various infective episodes and decision was made to manage him conservatively with best supportive care only.
This report highlight the fact that a rare but serious drug related complication associated with the use of sunitinib can be managed successfully with intensive outpatient hemodialysis without discontinuation of the medication in a patient who is already on maintenance HD. The limitation is this a single case report in 1 patient. Nevertheless, it provides insight on possible management option for continuation of sunitinib in the case of hyperammonaemia encephalopathy in a hemodialysis patient.
Author contributions
Conceptualization: Sabrina Haroon, Stephanie Ko, Titus Lau.
Visualization: Sabrina Haroon, Titus Lau.
Writing – original draft: Sabrina Haroon, Stephanie Ko.
Writing – review & editing: Sabrina Haroon, Stephanie Ko, Alvin Wong, Tan Poh Seng, Evan Lee, Titus Lau.
Abbreviations: CT = computed tomography, ED = emergency department, ESRD = end stage renal disease, HCV = hepatitis C, HD = hemodialysis, HE = hyperammonemia encephalopathy, PDGF = platelet derived growth factor, RCC = renal cell carcinoma, TKI = tyrosine kinase inhibitor, VEGF = vascular endothelial growth factor.
How to cite this article: Haroon S, Ko S, Wong A, Tan PS, Lee E, Lau T. Sunitinib-associated hyperammonemic encephalopathy successfully managed with higher intensity conventional hemodialysis: a case report. Medicine. 2021;100:5(e24313).
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Recovered | ReactionOutcome | CC BY | 33592876 | 19,002,656 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute myelomonocytic leukaemia'. | Transformation from acute promyelocytic leukemia to acute myeloid leukemia with a CEBPA double mutation: A case report and review of the literature.
BACKGROUND
The transformation of acute promyelocytic leukemia (APL) to acute mononuclear leukemia during treatment is a rare clinical phenomenon, and no CCAAT/enhancer-binding protein alpha (CEBPA) double mutations have been reported.
A 42-year-old male was hospitalized for ecchymosis of the left lower limb for more than 1 month, gingival bleeding, and fatigue for 10 days, with aggravation of symptoms for 2 days.
METHODS
A diagnosis of APL was based on bone marrow (BM) morphology, immunophenotyping, fusion gene analysis, and fluorescence in situ hybridization. At a 1-year follow-up of maintenance treatment, he developed thrombocytopenia and was diagnosed with acute myeloid leukemia (AML) with a CEBPA double mutation by BM morphology, immunotyping, chromosomal analysis, polymerase chain reaction, and next generation sequencing.
METHODS
Complete remission of APL was achieved after all-trans retinoic acid and arsenic trioxide double induction therapy, followed by 2 cycles of mitoxantrone and cytarabine, and 1 cycle of idarubicin and cytarabine. Thereafter, sequential maintenance therapy of arsenic trioxide + all-trans retinoic acid + methotrexate was started. In the fourth cycle of maintenance therapy, APL was transformed into AML with a CEBPA double mutation. After 1 cycle of idarubicin and cytarabine, the patient achieved complete remission and received 3 cycles of idarubicin and cytarabine and three cycles of high-dose cytarabine as consolidation therapy.
RESULTS
At present, the patient is in continuous remission with minimal residual disease negative for both of APL and AML.
CONCLUSIONS
AML with a CEBPA double mutation after APL treatment is very rare, thus the prognosis of this event will require further observation.
1 Introduction
Acute promyelocytic leukemia (APL) is a common subtype of acute myeloid leukemia (AML) and was formerly one of the most fatal forms of AML. The introduction of all-trans retinoic acid (ATRA) in combination with arsenic trioxide (ATO) and other chemotherapies has resulted in complete remission rates of >90% and long-term remission rates of >80%.[1] However, a very small number of leukemia subtypes can undergo disease transformation in response to chemotherapy or develop treatment-related secondary leukemia, which may be insensitive to chemotherapy, resulting in a poor prognosis. Hence, the clinical diagnosis and treatment of APL remain challenging. Here, we report a case of acute myelomonocytic leukemia with a double mutation to the CCAAT/enhancer-binding protein alpha (CEBPA) gene during maintenance therapy for APL and include a review of the current literature.
2 Case report
The patient was a 42-year-old male with no previous exposure to industrial toxins or radioactive substances. In November 2018, he was hospitalized for ecchymosis of the left lower limb for more than 1 month, gingival bleeding, and fatigue for 10 days, with aggravation for 2 days. On physical examination, the patient appeared anemic with scattered spots of bleeding of the mucosa and the skin over the whole body, no abnormality in heart rhythm or lung auscultation, a soft abdomen, no palpation of the liver or spleen under the ribs, and no edema of either lower limb. The findings of initial blood chemistry analysis were as follows: white blood cell count, 8.1 × 109/L; hemoglobin concentration, 69 g/L; platelet count, 16 × 109/L; prothrombin time, 14.6 s, activated partial thromboplastin time, 21.4 s; thrombin time, 21.5 s; K+, 3.71 mmol/L; Na+, 141 mmol/L; Ca2+, 1.89 mmol/L; γ-glutamine acylase, 144 U/L; total protein, 57.2 g/L; and albumin, 33.2 g/L. Bone marrow (BM) analysis revealed abnormal promyelocytes (89.2%) of different sizes with quasi-round shapes and tumor-like processes on the edge of the cytoplasm, medium amounts of cytoplasm, blue staining, purplish red granules in the cytoplasm, round nuclei, visible depressions, loose and fine chromatin, and visible nucleoli. In addition, erythroid differentiation was inhibited, megakaryocytes were absent, and platelets were rare (Fig. 1A). Fluorescence in situ hybridization of the BM showed that 68% of the 400 cells analyzed within the detection range revealed the presence of the PML/RARa fusion gene (Fig. 2). Further genetic screening revealed mutations to NRAS (NM_002524,cxon2:c.G35A:p.G120rs121913237) and TET (NM_001127208,cxon11:c.A5284G:p.11762Y). Flow cytometry analysis of the BM revealed the presence of abnormal cells that were positive for CD117, CD13, CD33, CD38, CD64, CD123, CD58, and cMPO, with partial expression of CD71, but negative for CD19, CD3, and CD34. Based on these findings, the patient was diagnosed with APL (medium-risk group). After ATRA + ATO double induction therapy, the patient received 2 cycles of ATRA + mitoxantrone and cytarabine, and one cycle of ATRA + idarubicin and cytarabine. Afterward, the patient was negative for the PML-RARα fusion gene. Following remission, intrathecal chemotherapy was administered to prevent the onset of central nervous system leukemia. On April 2, 2019, the patient started an alternating maintenance treatment regimen of ATO + ATRA + methotrexate. Before the fourth cycle of maintenance therapy on January 27, 2020, a BM examination and fusion gene analysis revealed complete remission of APL. On April 14, 2020, during the methotrexate regimen, the results of a routine blood test were as follows: white blood cell count, 4.01 × 109/L; percentage of monocytes, 15%; hemoglobin concentration, 56 g/L; platelet count 76 × 109/L; prothrombin time, 11.0 s; activated partial thromboplastin time, 31.5 s; thrombin time, 16.1 s; K+, 4.35 mmol/L; Ca2+, 2.31 mmol/L; alanine aminotransferase, 12 U/L; aspartate transaminase, 14 U/L; creatinine, 66 μmol/L, total protein, 57.2 g/L; and albumin, 45.3 g/L. A physical examination revealed no anemia, no sites of bleeding on the skin or mucosa, no abnormality in heart rhythm or lung auscultation, a soft abdomen, liver and spleen not palpable under the ribs, and no edema of either lower limb. The patient had no symptoms of altered consciousness at that time, so a bone puncture was performed immediately. BM morphological analysis revealed that 31.0% of the monocytes were primitive and immature with varied cell sizes, medium to rich cytoplasm, large nuclei, fine chromatin that was twisted and folded, visible nucleoli, granulocyte content of 6.5%, some vacuoles throughout the cytoplasm, active red proliferation, visible plasma, reticular cells with normal morphologies, 237 megakaryocytes inone smear, and visible platelets (Fig. 1B). Flow cytometry revealed that 44.75% of the primitive immature cells were nucleated and positive for CD34, CD38, CD13, CD15, CD117, CD33, CD7, and HLA-DR, but negative for CD3 and CD19. Myeloid expression was abnormal, which conformed to the AML phenotype. The PML-RARα gene was negative by fluorescence in situ hybridization analysis. Qualitative detection of 38 fusion genes specific to leukemia was also negative. Gene mutation analysis by next generation sequencing identified an insertion mutation to the CEBPA gene (c.912_913insTTG (p.Lys304_Gln305insLeu; heterozygous mutation frequency, 28.5%) and a code shift mutation (c.326del (p.Pro109ArgfsTer51; heterozygous). BM cytogenetic studies revealed a normal karyotype of 46, xy (20). The combined results of the physical examination and laboratory results suggested a diagnosis of AML and acute myelomonocytic leukemia with a CEBPA double mutation (low risk group). Therefore, induction chemotherapy was started with a regimen of idarubicin and cytarabine (idarubicin at 10 mg/m2 on days 1–3; and cytarabine at 100 mg every 12 hour on days 1–7). Reexamination of the BM at 14 days after chemotherapy showed that the patient had achieved complete remission. Thereafter, the patient received 3 cycles of idarubicin and cytarabine, and 3 cycles of high-dose cytarabine as consolidation therapy. At present, the patient is in continuous remission with minimal residual disease for both APL and AML.
Figure 1 Bone marrow morphological characteristics of the patient at diagnosis of acute promyelocytic leukemia and conversion to acute myeloid leukemia. (A) Before transformation. (B) After transformation. (Gitter-Giemsa staining,× 1000).
Figure 2 FISH detection of PML-RARα in the patient at diagnosis of acute promyelocytic leukemia. About 68% of 400 analyzed cells exhibited a red-green fusion signal representing the translocation of PML (green) and RARα (red) (DAPI staining,×1000).
3 Discussion
It is rare for leukemia to undergo lineage transformation during clinical treatment and there is no clear evidence to confirm the underlying mechanism. Moreover, the development of secondary myeloid tumors after APL therapy is also very rare. For example, Montesinos et al[2] reported 17 cases of secondary myeloid tumors, including AML and myelodysplastic syndrome, among 918 APL patients after treatment. The cumulative 6-year incidence of secondary myeloid tumors was 2.2%, with a higher incidence in APL patients aged >35 years, while in the low risk group, common cytogenetic abnormalities included –5, –7, and 11q23 rearrangements. The prognosis of secondary treatment-related myeloid tumors in APL is often poor, with a median survival time of only 10 months. Although the pathogenesis of secondary treatment-related leukemia remains unclear, 3 main hypotheses have been proposed:
(i) the use of cytotoxic drugs, especially topoisomerase inhibitors, alkalinizing agents, and anthracyclines,[3,4] leading to changes in DNA structure and secondary changes, most of which are treatment-related myelodysplastic syndrome or AML;[5,6]
(ii) APL accompanied by other clones in the early stage of the disease, but masked by the dominant clones, as the application of ATRA, ATO, and chemotherapy eliminate abnormal promyelocytes, so that other clones have a better chance of survival; and
(iii) the inherent lineage plasticity of primitive leukemia cells determines the potential for reprogramming under lineage-specific pressure[7,8] and more frequent lineage switching with specific genetic subtypes of leukemia, such as mixed lineage leukemia rearrangement, which may have greater inherent plasticity.[9] In the present case, the onset of secondary myeloid leukemia was earlier, as the switch to AML occurred only 17 months after complete remission of APL, which is a much shorter period than the median time of 44 months reported in the literature.[2] A retrospective study conducted by Wang et al[6] reported treatment-related myeloid tumors in 67 cases that most commonly occurred at about 3 years after complete remission of APL. In view of the short period of remission during treatment in this case, it was difficult to differentiate treatment-related secondary myeloid tumor formation from APL recurrence with a series of transitions. Moreover, a retrospective analysis of 651 AML patients conducted by Wang et al[10] found fewer favorable genetic molecular events in elderly patients with AML and secondary AML patients, such as a CEBPA double mutation, runx1-runxt1t1, etc. A double mutation to the CEBPA gene is detected in leukemia cells during AML transformation, and some cases before transformation to APL were accompanied with a double mutation to the CEBPA gene.[11] However, our patient was negative for the CEBPA double mutation at the first onset, which does not support the possibility of evolution from APL to AML. The CEBPA double mutation is often associated with a good prognosis of AML. Patients with a CEBPA double mutation are classified as low risk. However, in this patient, AML was secondary to APL. As reported in the literature, the prognosis of APL secondary to treated-acute myeloid leukemia is poor and survival is relatively short. Although the patient achieved complete remission after 1 course of chemotherapy, his long-term survival remains to be further investigated, as it is unclear whether the choice of follow-up consolidation therapy should be medium dose cytarabine-based chemotherapy or allogeneic hematopoietic stem cell transplantation.
The formation of a secondary myeloid tumor after APL treatment is a rare clinical phenomenon, which usually occurs at about 3 years after disease remission, although early development of a secondary myeloid tumor is not impossible. Also, it remains uncertain whether the prognosis of secondary AML with a CEBPA double mutation after APL is equivalent to that of newly diagnosed AML with a CEBPA double mutation, thus additional clinical cases are needed. The mechanism underlying secondary AML after APL therapy is unknown, but it is believed that with the development of genetic cytology and the accumulation of clinical cases, more accurate mechanisms will be identified and individualized prevention and treatment regimens will be clinically available.
Author contributions
Conceptualization: Guifang Ouyang.
Data curation: Ye Sun, Chong Wang, Yongcheng Sun, Jiaping Wang, Lixia Sheng.
Formal analysis: Chunmeng Rong, An Wu.
Funding acquisition: Lixia Sheng.
Methodology: Lixia Sheng.
Writing – original draft: Ye Sun.
Writing – review & editing: Lixia Sheng.
Abbreviations: AML = acute myeloid leukemia, APL = acute promyelocytic leukemia, ATO = arsenic trioxide, ATRA = all-trans retinoic acid, BM = bone marrow, CEBPA = CCAAT/enhancer-binding protein alpha.
How to cite this article: Sun Y, Wang C, Sun Y, Wang J, Rong C, Wu A, Ouyang G, Sheng L. Transformation from acute promyelocytic leukemia to acute myeloid leukemia with a CEBPA double mutation: a case report and review of the literature. Medicine. 2021;100:5(e24385).
This work was supported by grants from the National Nature Science Foundation of China (grant no. 81401321), the Basic Public Welfare Research Project of Zhejiang Province (grant no. LGF19H080002), the Science Research Project of Medicine and Hygiene of Zhejiang province (grant no. 2018PY052), and the Public Welfare Science and Technology Project of Ningbo (grant no. 2019C50068).
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
The study protocol was approved by the Ethics Review Committee of Ningbo First Hospital.
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
The authors have no conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | ARSENIC TRIOXIDE, CYTARABINE, IDARUBICIN HYDROCHLORIDE, METHOTREXATE, MITOXANTRONE HYDROCHLORIDE, TRETINOIN | DrugsGivenReaction | CC BY | 33592885 | 19,061,121 | 2021-02-05 |
What was the outcome of reaction 'Acute myelomonocytic leukaemia'? | Transformation from acute promyelocytic leukemia to acute myeloid leukemia with a CEBPA double mutation: A case report and review of the literature.
BACKGROUND
The transformation of acute promyelocytic leukemia (APL) to acute mononuclear leukemia during treatment is a rare clinical phenomenon, and no CCAAT/enhancer-binding protein alpha (CEBPA) double mutations have been reported.
A 42-year-old male was hospitalized for ecchymosis of the left lower limb for more than 1 month, gingival bleeding, and fatigue for 10 days, with aggravation of symptoms for 2 days.
METHODS
A diagnosis of APL was based on bone marrow (BM) morphology, immunophenotyping, fusion gene analysis, and fluorescence in situ hybridization. At a 1-year follow-up of maintenance treatment, he developed thrombocytopenia and was diagnosed with acute myeloid leukemia (AML) with a CEBPA double mutation by BM morphology, immunotyping, chromosomal analysis, polymerase chain reaction, and next generation sequencing.
METHODS
Complete remission of APL was achieved after all-trans retinoic acid and arsenic trioxide double induction therapy, followed by 2 cycles of mitoxantrone and cytarabine, and 1 cycle of idarubicin and cytarabine. Thereafter, sequential maintenance therapy of arsenic trioxide + all-trans retinoic acid + methotrexate was started. In the fourth cycle of maintenance therapy, APL was transformed into AML with a CEBPA double mutation. After 1 cycle of idarubicin and cytarabine, the patient achieved complete remission and received 3 cycles of idarubicin and cytarabine and three cycles of high-dose cytarabine as consolidation therapy.
RESULTS
At present, the patient is in continuous remission with minimal residual disease negative for both of APL and AML.
CONCLUSIONS
AML with a CEBPA double mutation after APL treatment is very rare, thus the prognosis of this event will require further observation.
1 Introduction
Acute promyelocytic leukemia (APL) is a common subtype of acute myeloid leukemia (AML) and was formerly one of the most fatal forms of AML. The introduction of all-trans retinoic acid (ATRA) in combination with arsenic trioxide (ATO) and other chemotherapies has resulted in complete remission rates of >90% and long-term remission rates of >80%.[1] However, a very small number of leukemia subtypes can undergo disease transformation in response to chemotherapy or develop treatment-related secondary leukemia, which may be insensitive to chemotherapy, resulting in a poor prognosis. Hence, the clinical diagnosis and treatment of APL remain challenging. Here, we report a case of acute myelomonocytic leukemia with a double mutation to the CCAAT/enhancer-binding protein alpha (CEBPA) gene during maintenance therapy for APL and include a review of the current literature.
2 Case report
The patient was a 42-year-old male with no previous exposure to industrial toxins or radioactive substances. In November 2018, he was hospitalized for ecchymosis of the left lower limb for more than 1 month, gingival bleeding, and fatigue for 10 days, with aggravation for 2 days. On physical examination, the patient appeared anemic with scattered spots of bleeding of the mucosa and the skin over the whole body, no abnormality in heart rhythm or lung auscultation, a soft abdomen, no palpation of the liver or spleen under the ribs, and no edema of either lower limb. The findings of initial blood chemistry analysis were as follows: white blood cell count, 8.1 × 109/L; hemoglobin concentration, 69 g/L; platelet count, 16 × 109/L; prothrombin time, 14.6 s, activated partial thromboplastin time, 21.4 s; thrombin time, 21.5 s; K+, 3.71 mmol/L; Na+, 141 mmol/L; Ca2+, 1.89 mmol/L; γ-glutamine acylase, 144 U/L; total protein, 57.2 g/L; and albumin, 33.2 g/L. Bone marrow (BM) analysis revealed abnormal promyelocytes (89.2%) of different sizes with quasi-round shapes and tumor-like processes on the edge of the cytoplasm, medium amounts of cytoplasm, blue staining, purplish red granules in the cytoplasm, round nuclei, visible depressions, loose and fine chromatin, and visible nucleoli. In addition, erythroid differentiation was inhibited, megakaryocytes were absent, and platelets were rare (Fig. 1A). Fluorescence in situ hybridization of the BM showed that 68% of the 400 cells analyzed within the detection range revealed the presence of the PML/RARa fusion gene (Fig. 2). Further genetic screening revealed mutations to NRAS (NM_002524,cxon2:c.G35A:p.G120rs121913237) and TET (NM_001127208,cxon11:c.A5284G:p.11762Y). Flow cytometry analysis of the BM revealed the presence of abnormal cells that were positive for CD117, CD13, CD33, CD38, CD64, CD123, CD58, and cMPO, with partial expression of CD71, but negative for CD19, CD3, and CD34. Based on these findings, the patient was diagnosed with APL (medium-risk group). After ATRA + ATO double induction therapy, the patient received 2 cycles of ATRA + mitoxantrone and cytarabine, and one cycle of ATRA + idarubicin and cytarabine. Afterward, the patient was negative for the PML-RARα fusion gene. Following remission, intrathecal chemotherapy was administered to prevent the onset of central nervous system leukemia. On April 2, 2019, the patient started an alternating maintenance treatment regimen of ATO + ATRA + methotrexate. Before the fourth cycle of maintenance therapy on January 27, 2020, a BM examination and fusion gene analysis revealed complete remission of APL. On April 14, 2020, during the methotrexate regimen, the results of a routine blood test were as follows: white blood cell count, 4.01 × 109/L; percentage of monocytes, 15%; hemoglobin concentration, 56 g/L; platelet count 76 × 109/L; prothrombin time, 11.0 s; activated partial thromboplastin time, 31.5 s; thrombin time, 16.1 s; K+, 4.35 mmol/L; Ca2+, 2.31 mmol/L; alanine aminotransferase, 12 U/L; aspartate transaminase, 14 U/L; creatinine, 66 μmol/L, total protein, 57.2 g/L; and albumin, 45.3 g/L. A physical examination revealed no anemia, no sites of bleeding on the skin or mucosa, no abnormality in heart rhythm or lung auscultation, a soft abdomen, liver and spleen not palpable under the ribs, and no edema of either lower limb. The patient had no symptoms of altered consciousness at that time, so a bone puncture was performed immediately. BM morphological analysis revealed that 31.0% of the monocytes were primitive and immature with varied cell sizes, medium to rich cytoplasm, large nuclei, fine chromatin that was twisted and folded, visible nucleoli, granulocyte content of 6.5%, some vacuoles throughout the cytoplasm, active red proliferation, visible plasma, reticular cells with normal morphologies, 237 megakaryocytes inone smear, and visible platelets (Fig. 1B). Flow cytometry revealed that 44.75% of the primitive immature cells were nucleated and positive for CD34, CD38, CD13, CD15, CD117, CD33, CD7, and HLA-DR, but negative for CD3 and CD19. Myeloid expression was abnormal, which conformed to the AML phenotype. The PML-RARα gene was negative by fluorescence in situ hybridization analysis. Qualitative detection of 38 fusion genes specific to leukemia was also negative. Gene mutation analysis by next generation sequencing identified an insertion mutation to the CEBPA gene (c.912_913insTTG (p.Lys304_Gln305insLeu; heterozygous mutation frequency, 28.5%) and a code shift mutation (c.326del (p.Pro109ArgfsTer51; heterozygous). BM cytogenetic studies revealed a normal karyotype of 46, xy (20). The combined results of the physical examination and laboratory results suggested a diagnosis of AML and acute myelomonocytic leukemia with a CEBPA double mutation (low risk group). Therefore, induction chemotherapy was started with a regimen of idarubicin and cytarabine (idarubicin at 10 mg/m2 on days 1–3; and cytarabine at 100 mg every 12 hour on days 1–7). Reexamination of the BM at 14 days after chemotherapy showed that the patient had achieved complete remission. Thereafter, the patient received 3 cycles of idarubicin and cytarabine, and 3 cycles of high-dose cytarabine as consolidation therapy. At present, the patient is in continuous remission with minimal residual disease for both APL and AML.
Figure 1 Bone marrow morphological characteristics of the patient at diagnosis of acute promyelocytic leukemia and conversion to acute myeloid leukemia. (A) Before transformation. (B) After transformation. (Gitter-Giemsa staining,× 1000).
Figure 2 FISH detection of PML-RARα in the patient at diagnosis of acute promyelocytic leukemia. About 68% of 400 analyzed cells exhibited a red-green fusion signal representing the translocation of PML (green) and RARα (red) (DAPI staining,×1000).
3 Discussion
It is rare for leukemia to undergo lineage transformation during clinical treatment and there is no clear evidence to confirm the underlying mechanism. Moreover, the development of secondary myeloid tumors after APL therapy is also very rare. For example, Montesinos et al[2] reported 17 cases of secondary myeloid tumors, including AML and myelodysplastic syndrome, among 918 APL patients after treatment. The cumulative 6-year incidence of secondary myeloid tumors was 2.2%, with a higher incidence in APL patients aged >35 years, while in the low risk group, common cytogenetic abnormalities included –5, –7, and 11q23 rearrangements. The prognosis of secondary treatment-related myeloid tumors in APL is often poor, with a median survival time of only 10 months. Although the pathogenesis of secondary treatment-related leukemia remains unclear, 3 main hypotheses have been proposed:
(i) the use of cytotoxic drugs, especially topoisomerase inhibitors, alkalinizing agents, and anthracyclines,[3,4] leading to changes in DNA structure and secondary changes, most of which are treatment-related myelodysplastic syndrome or AML;[5,6]
(ii) APL accompanied by other clones in the early stage of the disease, but masked by the dominant clones, as the application of ATRA, ATO, and chemotherapy eliminate abnormal promyelocytes, so that other clones have a better chance of survival; and
(iii) the inherent lineage plasticity of primitive leukemia cells determines the potential for reprogramming under lineage-specific pressure[7,8] and more frequent lineage switching with specific genetic subtypes of leukemia, such as mixed lineage leukemia rearrangement, which may have greater inherent plasticity.[9] In the present case, the onset of secondary myeloid leukemia was earlier, as the switch to AML occurred only 17 months after complete remission of APL, which is a much shorter period than the median time of 44 months reported in the literature.[2] A retrospective study conducted by Wang et al[6] reported treatment-related myeloid tumors in 67 cases that most commonly occurred at about 3 years after complete remission of APL. In view of the short period of remission during treatment in this case, it was difficult to differentiate treatment-related secondary myeloid tumor formation from APL recurrence with a series of transitions. Moreover, a retrospective analysis of 651 AML patients conducted by Wang et al[10] found fewer favorable genetic molecular events in elderly patients with AML and secondary AML patients, such as a CEBPA double mutation, runx1-runxt1t1, etc. A double mutation to the CEBPA gene is detected in leukemia cells during AML transformation, and some cases before transformation to APL were accompanied with a double mutation to the CEBPA gene.[11] However, our patient was negative for the CEBPA double mutation at the first onset, which does not support the possibility of evolution from APL to AML. The CEBPA double mutation is often associated with a good prognosis of AML. Patients with a CEBPA double mutation are classified as low risk. However, in this patient, AML was secondary to APL. As reported in the literature, the prognosis of APL secondary to treated-acute myeloid leukemia is poor and survival is relatively short. Although the patient achieved complete remission after 1 course of chemotherapy, his long-term survival remains to be further investigated, as it is unclear whether the choice of follow-up consolidation therapy should be medium dose cytarabine-based chemotherapy or allogeneic hematopoietic stem cell transplantation.
The formation of a secondary myeloid tumor after APL treatment is a rare clinical phenomenon, which usually occurs at about 3 years after disease remission, although early development of a secondary myeloid tumor is not impossible. Also, it remains uncertain whether the prognosis of secondary AML with a CEBPA double mutation after APL is equivalent to that of newly diagnosed AML with a CEBPA double mutation, thus additional clinical cases are needed. The mechanism underlying secondary AML after APL therapy is unknown, but it is believed that with the development of genetic cytology and the accumulation of clinical cases, more accurate mechanisms will be identified and individualized prevention and treatment regimens will be clinically available.
Author contributions
Conceptualization: Guifang Ouyang.
Data curation: Ye Sun, Chong Wang, Yongcheng Sun, Jiaping Wang, Lixia Sheng.
Formal analysis: Chunmeng Rong, An Wu.
Funding acquisition: Lixia Sheng.
Methodology: Lixia Sheng.
Writing – original draft: Ye Sun.
Writing – review & editing: Lixia Sheng.
Abbreviations: AML = acute myeloid leukemia, APL = acute promyelocytic leukemia, ATO = arsenic trioxide, ATRA = all-trans retinoic acid, BM = bone marrow, CEBPA = CCAAT/enhancer-binding protein alpha.
How to cite this article: Sun Y, Wang C, Sun Y, Wang J, Rong C, Wu A, Ouyang G, Sheng L. Transformation from acute promyelocytic leukemia to acute myeloid leukemia with a CEBPA double mutation: a case report and review of the literature. Medicine. 2021;100:5(e24385).
This work was supported by grants from the National Nature Science Foundation of China (grant no. 81401321), the Basic Public Welfare Research Project of Zhejiang Province (grant no. LGF19H080002), the Science Research Project of Medicine and Hygiene of Zhejiang province (grant no. 2018PY052), and the Public Welfare Science and Technology Project of Ningbo (grant no. 2019C50068).
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
The study protocol was approved by the Ethics Review Committee of Ningbo First Hospital.
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
The authors have no conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Recovered | ReactionOutcome | CC BY | 33592885 | 19,061,121 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal death'. | Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus: A STROBE-compliant study.
Studies on predicting factors for adverse pregnancy outcomes (APOs) in Thai patients with systemic lupus erythematosus (SLE) are limited. This retrospective observation study determined APOs and their predictors in Thai patients with SLE.Medical records of pregnant SLE patients in a lupus cohort, seen from January 1993 to June 2017, were reviewed.Ninety pregnancies (1 twin pregnancy) from 77 patients were identified. The mean age at conception was 26.94 ± 4.80 years. At conception, 33 patients (36.67%) had active disease, 23 (25.56%) hypertension, 20 (22.22%) renal involvement, and 6 of 43 (13.95%) positive anti-cardiolipin antibodies or lupus anti-coagulants, and 37 (41.11%) received hydroxychloroquine. Nineteen patients (21.11%) had pregnancy loss. Of 71 successful pregnancies, 28 (31.11%) infants were full-term, 42 (46.67%) pre-term and 1 (11.11%) post-term; 19 (26.39%) were small for gestational age (SGA), and 38 (52.58%) had low birth weight (LBW). Maternal complications occurred in 21 (23.33%) pregnancies [10 (11.11%) premature rupture of membrane (PROM), 8 (8.89%) pregnancy induced hypertension (PIH), 4 (4.44%) oligohydramnios, 2 (2.22%) post-partum hemorrhage, and 1 (1.11%) eclampsia]. Patients aged ≥ 25 years at pregnancy and those ever having renal involvement had predicted pregnancy loss with adjusted odds ratio (AOR) [95% CI] of 4.15 [1.10-15.72], P = .036 and 9.21 [1.03-82.51], P = .047, respectively. Renal involvement predicted prematurity (6.02 [1.77-20.52, P = .004), SGA (4.46 [1.44-13.78], P = .009), and LBW in infants (10.01 [3.07-32.62], P < .001). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception protected against prematurity (0.11 [0.02-0.85], P = .034). Flares and hematologic involvement predicted PROM (8.45 [1.58-45.30], P = .013) and PIH (9.24 [1.70-50.24], P = .010), respectively. Cutaneous vasculitis (33.87 [1.05-1,094.65], P = .047), and renal (31.89 [6.66-152.69], P < .001), mucocutaneous (9.17 [1.83-45.90], P = .007) and hematologic involvement (128.00 [4.60-3,564.46], P = .004) during pregnancy predicted flare; while prednisolone (>10 mg/day) and immunosuppressive drug use at conception reduced that risk (0.08 [0.01-0.68, P = .021).APOs remain a problem in Thai pregnant SLE patients. Renal involvement and SLE flares were associated with the risk of APOs.
1 Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ systems, characterized by remission and relapse. The disease predominantly affects women of child bearing age. Pregnancy in SLE patients is a challenging issue in clinical practice because of its association with increasing adverse outcomes in both mother and fetus.[1,2] Pregnant women with SLE have a reportedly higher rate of spontaneous abortion, fetal loss, intra-uterine growth retardation, pre-term delivery, pregnancy induced hypertension (PIH), pre-eclampsia and flares. Furthermore, pregnancy in SLE patients can cause disease exacerbation or flare, which often requires increasing doses of corticosteroids and/or immunosuppressive drugs that can have adverse effects on mother and fetus.[3,4] Thus, it is suggested that pregnancy in SLE patients should be avoided if the patients have had active severe disease within the previous 6 months, or significant heart, lung, renal and central nervous system involvement.[3,4]
With progress made in understanding the clinical course of SLE, standard instruments that determine disease activity and flares have been developed, as well as progression in medical treatment that results in improved obstetrics care of pregnant SLE patients.[3,5] Pregnancy outcomes in SLE patients have been reported widely, however, data on pregnancy outcomes from Asian countries are very limited.[6–11]
The purpose of this study was to determine pregnancy outcomes and identify independent predicting factors for adverse pregnancy outcomes (APOs) from a lupus cohort of Thai pregnant patients with SLE.
2 Patients and methods
2.1 Patients and data source
The medical records of SLE patients in a lupus cohort seen between January 1993 and June 2017 at the Division of Rheumatology, Faculty of Medicine, Chiang Mai University, Thailand were reviewed. SLE was diagnosed according to the 1997 updating the American College of Rheumatology (ACR) revised criteria for the classification of SLE.[12] Pregnant SLE patients were identified. Clinical manifestations, laboratory investigations, treatment, and SLE disease activity were recorded from 6 months prior to conception (−6 M) until 6 weeks after termination of pregnancy or delivery or the post-partum period. Pregnancy data were recorded at the time of conception or when the pregnancy was documented. The data were captured at −6 M, 3 months prior to conception (−3 M), at the time of conception, 1st trimester, 2nd trimester, 3rd trimester, and the post-partum period. If the patients had more than 1 visit during each period, the mean SLE disease activity of each period was used for statistical analysis. Laboratory investigations, including complete blood counts, urine analysis, and renal and liver functions were recorded routinely. The 24-hour urine protein creatinine ratio (24hour UPCI) [urine protein in gm/day to urine creatinine in gm/day] was determined only in cases with lupus nephritis (urine protein >0.5 gm/day). SLE patients were followed up usually in the clinic at 1 to 3 month intervals, depending on SLE disease activity or other clinical encounters. If the patients had more than 1 pregnancy, each one was considered as a separate observation and counted as an individual case.
Patients in the clinic should have been in clinical remission or have stable low disease activity (prednisolone ≤10 mg/day without immunosuppressive drugs other than anti-malarial medication) for a minimum of 12 months to allow for pregnancy to occur. Those who developed mild to moderate flares during pregnancy were administered prednisolone at a dosage of up to 0.50 mg/kg/day, and those with severe flares received >0.50 to 1.00 mg/kg/day. Anti-malarial medication was given according to clinical indications, e.g., skin rashes, oral ulcers or alopecia. Immunosuppressive drugs, particularly azathioprine and cyclosporine, were given to cases of severe flares. Cases in which the patients received methotrexate, cyclophosphamide or mycophenolate mofetil at the time of pregnancy, had these immunosuppressive drugs discontinued immediately and replaced with azathioprine or cyclosporine.
2.2 SLE disease activity and flare assessment
The modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K)[13] was used in this study to determine SLE disease activity (as anti-dsDNA and complements were not routinely available at this institution). The severity of SLE disease activity was classified according to that of Abrahamowicz et al,[14] but the mSLEDAI-2K instrument was used instead of the original SLEDAI-2K; remission [mSLEDAI-2K = 0], mild disease activity [mSLEDAI-2K = 1–5], moderate disease activity [mSLEDAI-2K = 6–10], high disease activity [mSLEDAI-2K = 11–19] and very high disease activity [mSLEDAI-2K = ≥20]). The severity of SLE flare (mild or moderate flare and severe flare) followed the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE flare index (SFI).[15] As the physician global assessment (PGA) was not recorded routinely, the SFI was modified by excluding the PGA items (mSFI). Organ damage accrual was determined using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).[16]
2.3 Pregnancy outcomes
The definition of maternal complications (premature rupture of membrane [PROM], oligohydramnios, pregnancy induced hypertension [PIH], pre-eclampsia, eclampsia, and direct and indirect maternal death), and fetal outcomes (pregnancy loss, miscarriage or spontaneous abortion, intra-uterine fetal death, medical termination of pregnancy, pre-term delivery, term delivery, post-term delivery, neonatal death, small for gestational age [SGA], and infant birth weight) followed that of standard references.[17]
2.4 Ethical statement
This study was performed in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This study was approved by the Ethic Committee of the Faculty of Medicine, Chiang Mai University (no. 215/2017).
2.5 Statistical analysis
STATA 14.2 computer software (Stata Corporation, Texas USA) was used for data processing and statistical analysis. As some patients had more than 1 pregnancy, each one was considered individually for statistical analysis. Continuous variables were presented as mean ± standard deviation (SD) or median (min-max), with categorical variables presented as percent. The Student t test and Wilcoxon rank sum test were used to determine the differences between 2 independent samples of continuous variables. One-way analysis of variance (ANOVA) and the Kruskal–Wallis test were used for more than 2 samples, with normal and non-normal distribution, respectively. The Chi-Squared test or Fisher exact test was used to determine associations among the categorical variables, where appropriate. Firth's logistic regression was used to predict the odds ratio (OR) and 95% confidence intervals (95% CI) when the outcome contained cell counts of zero. Variables with a P value <.20 from univariate analysis were entered into multiple logistic regression analysis, and reported as adjusted odds ratio (AOR) and 95% CI. A P ≤ .05 was considered as being a statistically significant difference.
3 Results
3.1 Demographics and characteristics of pregnant SLE patients
From a cohort of 1167 female SLE patients, 90 pregnancies occurred from 77 patients (1, 2, and 3 pregnancies in 66, 9 and 2 patients, respectively). Their mean age at SLE onset and age at pregnancy was 21.63 ± 5.89 years and 26.94 ± 4.80 years, respectively. Pregnancies occurred at the time of SLE diagnosis, and < 5 years and ≥ 5 years after SLE diagnosis in 7 (7.78%), 49 (54.44%) and 34 (37.78%) pregnancies, respectively. Of the 90 pregnancies, 45 (50.00%), 25 (27.78%), and 20 (22.22%) were the first, second and third or more, respectively. Their mean cumulative ACR classification criteria and SDI score were 5.49 ± 1.15 and 0.40 ± 0.72, respectively. The mean ± SD mSLEDAI-2K score at −6 M and time of conception was 1.72 ± 3.22 and 1.90 ± 3.44, respectively. Active disease at the time of conception (mSLEDAI-2K score ≥ 0) was observed in 33 of 90 pregnancies (36.67%), and all of them were unplanned. Active organ involvement at the time of conception was renal (urine protein creatinine ratio >0.5) in 20 (22.22%) pregnancies, mucocutaneous lesions in 15 (16.67%), cutaneous vasculitis in 2 (2.22%), and arthritis and hematologic abnormalities in 1 (1.11%) of each.
Co-morbidities were seen as follows: hypertension in 23 (25.56%) pregnancies, dyslipidemia in 8 (8.89%), thalassemia in 7 (7.78%), anti-phospholipid syndrome in 3 (3.33%), diabetes mellitus in 1 (1.11%), and others in 19 (21.11%) [hepatitis C virus infection, avascular necrosis of the hip, stroke and atrial secundum defect, and past history of cryptococcal meningitis, pneumocystis jirovecii pneumonia, and past treatment of pulmonary tuberculosis]. None of the patients drank alcohol or smoked.
Antinuclear antibodies (ANA) were observed in 89 pregnancies (98.89%). Anti-double stranded DNA (anti-dsDNA), anti-Smith (anti-Sm), anti-cardiolipin (ACL), lupus coagulants (LAC), and anti-Ro (anti-Ro) antibodies were observed in 50 of 85 (58.82%), 1 of 12 (8.33%), 4 of 58 (6.89%), 3 of 42 (7.14%), and 21 of 46 (45.65%) pregnancies that had been tested, respectively.
Patients in 15 of the 90 pregnancies (16.67%) had not received any specific SLE medication at the time of conception. Patients in 57 (63.33%) of the pregnancies received prednisolone at a dose of ≤10 mg/day, and in 16 (17.78%) at ≥ 10 mg/day, with the mean dosage of 10.77 ± 11.73 mg/day. Patients also received hydroxychloroquine (HCQ) in 37 (41.11%) pregnancies, cyclophosphamide in 6 (6.67%), mycophenolate mofetil in 4 (4.40%), azathioprine in 10 (11.11%), and cyclosporine in 3 (3.33%). Both cyclophosphamide and mycophenolate mofetil were switched to azathioprine or cyclosporine when the pregnancy was documented.
3.2 Overall pregnancy outcomes
Of the 90 pregnancies, 19 (21.11%) were lost (spontaneous abortion in 12 (13.33%) [7 in the 1st trimester and 5 in the 2nd], medical termination in 5 (5.56%) [1 in the 1st trimester and 4 in the 2nd], and dead fetus in the utero (1 in each 2nd and 3rd trimester). Of the 71 (78.89%) successful pregnancies, 28 (31.11%) were full-term, 42 (46.67%) pre-term (1 twin pregnancy), and 1 (1.11%) was a post-term delivery, resulting in 72 live born infants. Mode of delivery among the live births were vaginal in 52 (73.24%) and cesarean section in 19 (26.76%). The mean ± SD duration of pregnancy with live born infants was 35.76 ± 3.58 weeks. The mean ± SD weight of the 72 live born infants was 2,367.33 ± 640.30 gm (range 720–3853 gm), with normal birth weight (≥2500 gm), low birth weight (LBW) [1500–2499 gm], and very low birth weight (VLBW) [<1500 gm] in 34 (47.22%), 30 (41.67%) and 8 (11.11%) infants, respectively. SGA infants occurred in 19 live born infants (26.39%). There was 1 neonatal death (1.11%). No infants had congenital anomalies or completed heart block.
Maternal complications occurred in 21 (23.33%) pregnancies. PROM occurred in 10 (11.11%) pregnancies, PIH in 8 (8.89%), oligohydramnios in 4 (4.44%), post-partum hemorrhage in 2 (2.22%), and eclampsia in 1 (1.11%). One concomitant PROM and oligohydramnios, PROM and post-partum hemorrhage, PROM and PIH, and PIH and eclampsia occurred in each pregnancy. There were no cases of anti-partum hemorrhage, post-partum endometritis, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), pre-eclampsia or maternal death. Thirty seven flares (41.11%) were mild to moderate and severe in 9 (24.32%) and 28 (75.68%) pregnancies, respectively.
3.3 Effect of renal involvement, hypertension, presence of anti-cardiolipin antibodies and/or lupus anti-coagulants and SLE flares on pregnancy outcomes
The effects of renal involvement, hypertension, and the presence of ACL/LAC and SLE flares on pregnancy outcomes were determined and are shown in Table 1.
Table 1 Effect of active renal involvement during pregnancy, hypertension at the time of conception, presence of anti-phospholipid antibodies and SLE flares during pregnancy on pregnancy outcomes.
Renal involvement Hypertension ACL/LAC Flares
Yes No P value Yes No P value Yes No P value Yes No P value
Successful pregnancy, n (%) 30 (75.00) 41 (82.00) .419 16 (69.57) 55 (82.09) .204 4 (66.67) 32 (86.49) .248 32 (86.49) 39 (73.58) .140
Pregnancy duration, in weeks, mean ± SD 34.34 ± 4.50 36.80 ± 2.26 .009 35.60 ± 2.47 35.81 ± 3.86 .838 38.50 ± 2.52 36.20 ± 3.45 .209 34.43 ± 3.91 36.85 ± 2.90 .004
Fetal weight, in grams, mean ± SD 2,029.52 ± 611.82 2,622.76 ± 540.06 <.001 2,147.65 ± 580.34 2,435.24 ± 647.59 .106 2,680.00 ± 557.32 2,379.94 ± 749.66 .447 2097.58 ± 615.13 2595.59 ± 575.07 .001
Fetal outcomes
Live birth, n (%) 31 (75.61)∗ 41 (82.00) .456 17 (70.83)∗ 55 (82.09) .244 4 (66.67) 32 (86.49) .248 33 (86.84)∗ 39 (73.58) .125
Term, n (%) 6 (15.00) 22 (44.00) .003 7 (30.43) 21 (31.34) .935 3 (50.00) 14 (37.84) .666 9 (24.32) 19 (35.85) .245
Pre-term, n (%) 24 (58.54)∗ 19 (38.00) .051 10 (41.67)∗ 33 (49.25) .523 1 (16.67) 17 (45.95) .177 24 (63.16)∗ 19 (35.85) .010
Post-term, n (%) 1 (2.50) 0 .444 0 1 (1.49) >.999 0 1 (2.70) >.999 0 1 (1.89) >.999
Total fetal loss, n (%) 10 (25.00) 9 (18.00) .419 7 (30.43) 12 (17.91) .204 2 (33.33) 5 (13.51) .248 5 (13.51) 14 (26.42) .140
Spontaneous abortion, n (%) 6 (15.00) 6 (12.00) .677 4 (17.39) 8 (11.94) .507 1 (16.67) 4 (10.81) .547 3 (8.11) 9 (16.98) .223
Medical termination, n (%) 2 (5.00) 3 (6.00) >.999 2 (8.70) 3 (4.48) .599 1 (16.67) 1 (2.70) .262 1 (2.70) 4 (7.55) .645
Dead fetus in the utero, n (%) 2 (5.00) 0 .195 1 (4.35) 1 (1.49) .448 0 0 1 (2.70) 1 (1.89) >.999
Neonatal death, n (%) 1 (2.50) 0 .444 1 (4.35) 0 .256 0 1 (2.70) >.999 1 (2.70) 0 .411
SGA, n (%) 13 (32.50) 6 (12.00) .018 7 (30.43) 12 (17.91) .204 1 (16.67) 12 (32.43) .649 11 (29.73) 8 (15.09) .094
LBW (< 2500 grams), n (%) 25 (60.98)∗ 13 (26.00) .001 11 (45.83)∗ 27 (40.30) .637 1 (16.67) 18 (48.65) .143 23 (60.53)∗ 15 (28.30) .002
Maternal complications†, n (%) 30 (75.00) 15 (30.00) <.001 16 (69.57) 29 (43.28) .030 2 (33.33) 18 (48.65) .669 37 (100.00) 8 (15.09) <.001
PROM, n (%) 6 (15.00) 4 (8.00) .294 1 (4.35) 9 (13.43) .232 0 4 (10.81) >.999 8 (21.62) 2 (3.77) .008
Oligohydramnios, n (%) 3 (7.50) 1 (2.00) .319 1 (4.35) 3 (4.48) >.999 0 2 (5.41) >.999 2 (5.41) 2 (3.77) >.999
PPH, n (%) 0 2 (4.00) .501 0 2 (2.99) >.999 0 1 (2.70) >.999 0 2 (3.77) .510
PIH, n (%) 5 (12.50) 3 (6.00) .282 1 (4.35) 7 (10.45) .375 0 3 (8.11) >.999 5 (13.51) 3 (5.66) .198
Eclampsia, n (%) 0 1 (2.00) >.999 0 1 (1.49) >.999 0 1 (2.70) >.999 0 1 (1.89) >.999
Flares, n (%) 27 (67.50) 10 (20.00) <.001 14 (60.87) 23 (34.33) .026 2 (33.33) 14 (37.84) >.999
Forty pregnancies were shown to have active nephritis during pregnancy. Active renal involvement occurred in 30, 30, and 26 pregnancies during the 1st, 2nd, and 3rd trimester, respectively, which was significantly higher than the 20 pregnancies seen at the time of conception (P < .001). When compared to patients without renal involvement during pregnancy, those with it had significantly shorter mean pregnancy duration (34.34 ± 4.40 weeks vs 36.80 ± 2.26 weeks, P = .003), lower fetal birth weight among live births (2029.52 ± 611.82 gm vs 2622.76 ± 540.06 gm, P < .001), and a higher proportion of LBW infants (60.98% vs 26.00%, P < .001), and SGA infants (32.50% vs 12.00%, P = .018). Although the proportion among live birth infants was not different, those with renal involvement had a significantly lower proportion of full-term infants (15.00% vs 44.00%, P = .003) and almost significantly higher proportion of pre-term infants (58.54% vs 38.00%, P = .051). There was no statistically significant difference in fetal loss among the 2 groups. The maternal complications in those with renal involvement during pregnancy were significantly higher (75.00% vs 30.00%, P < .001), which was due to a higher proportion of patients with SLE flare (67.50% vs 20.00%, P < .001). Other maternal complications, including PROM, oligohydramnios and PIH, also were higher proportionally, but they did not reach statistical significance.
Overall, there were no statistically significant differences in adverse fetal outcomes among patients with or without hypertension during pregnancy. However, pregnancy outcomes among patients with hypertension tended to have a lower proportion of live birth infants, and higher proportion of fetal loss (both spontaneous and medical terminations), SGA and LBW among full-term infants, and a lower mean fetal birth weight. Maternal complications were significantly higher in patients with hypertension (69.57% vs 43.28%, P = .030), which was due mainly to the higher proportion of those with SLE flares (60.48% vs 34.33%, P = .026). It was interesting that the proportion of PROM and PIH was lower in patients with hypertension, but with no significance.
The effect of anti-cardiolipin antibodies (ACL) and lupus anticoagulant (LAC) tests on pregnancy outcomes also was determined. Unfortunately, these 2 tests were determined in only approximately 50% of the patients. ACA and LAC were positive in a small proportion of the patients (4 of 58 or 6.89% and 3 of 42 or 7.14% of those tested, respectively). Overall, there was no statistically significant difference between either the fetal and maternal outcomes among pregnant patients with positive ACL/LAC or those without; however, those with positive ACL/LAC tended to have a lower proportion of live births and full-term birth infants, and higher proportion of fetal losses. It was interesting that the proportion of SGA, LBW, and maternal complication in the ACL/LAC positive patients also was lower, but without statistical significance. This might be due to the small number of patients in this group.
The effect of flares on pregnancy outcomes also was determined. When compared to SLE patients without flares during pregnancy, those with them had significantly shorter duration of pregnancy (34.43 ± 3.91 weeks vs 36.85 ± 2.90 weeks, P = .004), and lower mean fetal weight among live births (2097.58 ± 615.13 gm vs 2595.59 ± 575.07 gm, P = .001). Although the proportion of live birth infants and fetal loss was no different between the 2 groups, the patients with flares had a significantly higher proportion of pre-term births and LBW infants (63.16% vs 35.85%, P = .010, and 60.53% vs 28.30%, P = .002, respectively). The proportion of SGA infants also was higher, but did not reach statistical significance (29.73% vs 15.09%, P = .094). The adverse maternal outcomes were higher (100.00% vs 15.09%, P < .001), particularly of PROM (21.62% vs 3.77%, P < .008).
3.4 Effect of HCQ used on pregnancy outcomes
The effect of HCQ used during pregnancy on pregnancy outcomes was determined. Overall, there was no statistically significant difference in fetal outcomes among patients who did or did not receive HCQ during pregnancy. However, infants born to mothers who used HCQ tended to have a higher proportion of full term births (37.84% vs 26.42%, P = .249), and lower proportion of SGA (16.22% vs. 24.53%, P = .342) and LBW (36.84% vs 45.28%, P = .421). The proportion of live birth infants and fetal loss was similar between the 2 groups (78.95% vs 79.25%, P = .972, and 21.62% vs. 20.75%, P = .921, respectively). The proportion of maternal complications was lower among patients who received HCQ, and it almost reached statistical significance (37.84% vs 58.49%, P = .054). The proportion of maternal PROM, PIH and flares in the HCQ group also was lower, but did not reach statistical significance (5.41% vs 15.09%, P = .150; 5.41% vs 11.32%, P = .332, and 32.43% vs 47.17%, P = .162, respectively).
3.5 Pregnancy outcomes according to period of pregnancy, and between the first and subsequence pregnancy
The pregnancy outcomes according to the period of pregnancy (1993–2001, 2002–2009, and 2010–2017) were determined. Overall, there was no statistically significant difference in fetal or maternal outcomes between each pregnancy period. However, when comparing the pregnancy outcomes between 2010–2017, 2002–2009, and 1993–2001, fetal outcomes among pregnancies during 2010–2017 tended to have a higher proportion of live births (80.85% vs 76.00% vs 78.95%, P = .890), full-term birth infants (36.17% vs 32.00% vs 16.67%, P = .313), but with a lower proportion of pre-term birth infants (42.55% vs 44.00% vs 63.16%, P = .294), and pregnancy loss (19.15% vs 24.00% vs 22.22%, P = .884). They also had had a higher proportion of SGA and LBW (29.79% vs 16.00% vs 5.56%, P = .070, and 48.94% vs 36.00% vs 31.58%, P = .342, respectively). The proportion of maternal complications was similar (48.94% vs 48.00% vs 55.56%, P = .868); but with a tendency for decreased proportion of PROM (8.51% vs 12.00% vs 16.67%, P = .495), PIH (8.51% vs 4.00% vs 16.67%, P = .382) and SLE flares (38.30% vs 44.00% vs 44.44%, P = .851).
The pregnancy outcomes between patients with a first pregnancy and subsequent pregnancies also were compared. Similarly, there was no significant difference in fetal and maternal outcomes between the 2 groups. However, fetal outcomes in subsequent pregnancy groups tended to have a lower proportion of live births (73.91% vs 84.44%, P = .217), full-term births (24.44% vs 37.78%, P = .172), SGA (17.78% vs 24.44%, P = .438) and LBW infants (36.96% vs 46.67%, P = .348), but higher proportion of fetal loss (26.67% vs 15.56%, P = .197). Maternal complications tended to be lower (46.67% vs 53.33%, P = .527), which was due mainly to decreased proportion of SLE flares (37.78% vs 44.44%, P = .520). The rate of caesarean section was significantly higher among subsequent pregnancies (39.39% vs 15.79%, P = .025).
3.6 Predicting factors for adverse pregnancy outcomes
In order to determine independent predicting factors for APOs, the clinical characteristics that associated with adverse fetal outcomes (pregnancy loss, prematurity, SGA and LBW), and adverse maternal outcomes (PROM, PIH and flare) were compared and are shown in Tables 2 and 3, respectively.
Table 2 Comparison of clinical characteristics of adverse fetal outcomes in pregnant SLE patients.
Successful pregnancy Pregnancy loss Pre-maturity Full term + post term SGA Non-SGA LBW Normal BW
Characteristics (n = 71) (n = 19) P value (n = 42) (n = 29) P value (n = 19) (n = 52) P value (n = 37) (n = 34) P value
Age at pregnancy (in years), mean ± SD 26.30 ± 4.55 29.31 ± 5.09 .014 26.46 ± 4.73 26.07 ± 4.34 .726 25.09 ± 3.85 26.74 ± 4.73 .178 26.12 ± 4.61 26.50 ± 4.54 .726
Disease duration prior to conception (in years), mean ± SD 4.92 ± 5.01 6.99 ± 5.37 .081 4.38 ± 3.96 5.71 ± 6.21 .574 5.20 ± 4.26 4.82 ± 5.29 .451 4.54 ± 4.08 5.34 ± 5.89 .954
Co-morbidities
Hypertension, n (%) 16 (22.54) 7 (36.84) .204 9 (21.43) 7 (24.14) .788 7 (36.84) 9 (17.31) .081 10 (27.03) 6 (17.65) .345
Diabetes, n (%) 1 (1.41) 0 >.999 1 (2.38) 0 >.999 1 (5.26) 0 .268 1 (2.70) 0 >.999
Dyslipidemia, n (%) 5 (7.04) 3 (15.79) .234 3 (7.14) 2 (6.90) >.999 4 (21.05) 1 (1.92) .016 4 (10.81) 1 (2.94) .359
APS, n (%) 2 (2.82) 1 (5.26) .513 0 2 (6.90) .163 0 2 (3.85) >.999 0 2 (5.88) .226
ANA positive, n (%) 70 (98.59) 19 (100.00) >.999 41 (97.62) 29 (100.00) >.999 19 (100.00) 51 (98.08) >.999 37 (100.00) 33 (97.06) .479
Anti-dsDNA, n (%)∗ 41/67 (61.19) 9/18 (50.00) .392 26/40 (65.00) 15/27 (55.56) .436 13/19 (68.42) 28/48 (58.33) .445 25/37 (67.57) 16/30 (53.33) .234
Anti-Sm, n (%)∗ 0/11 1/1 (100.00) .083 0/7 0/4 0/2 0/9 0/6 0/5
ACL/LAC, n (%)∗ 4/36 (11.11) 2/7 (28.57) .248 1/18 (5.56) 3/18 (16.67) .603 1/13 (7.69) 3/23 (13.04) >.999 1/19 (5.26) 3/17 (17.65) .326
Anti-Ro, n (%)∗ 16/38 (42.11) 5/8 (62.50) .293 7/17 (41.18) 9/21 (42.86) .917 6/13 (46.15) 10/25 (40.00) .715 11/23 (47.83) 5/15 (33.33) .376
Anti-La, n (%)∗ 16/38 (42.11) 4/9 (44.44) .898 7/17 (41.18) 9/21 (42.86) .917 6/13 (46.15) 10/25 (40.00) .715 11/23 (47.83) 5/15 (33.33) .376
Pregnancy loss (ever), n (%) 23 (32.39) 9 (47.37) .226 12 (28.57) 11 (37.93) .407 6 (31.58) 17 (32.69) .929 11 (29.73) 12 (35.29) .617
Cumulative number of ACR criteria, mean ± SD 5.46 ± 1.11 5.58 ± 1.35 .704 5.38 ± 1.17 5.59 ± 1.02 .446 5.42 ± 1.02 5.48 ± 1.15 .842 5.35 ± 1.06 5.59 ± 1.16 .371
Disease activity (mSLEDAI-2K) at −6M, mean ± SD 1.34 ± 2.43 3.16 ± 5.05 .325 1.36 ± 2.44 1.31 ± 2.46 .960 1.42 ± 2.48 1.31 ± 2.44 .874 1.38 ± 2.53 1.29 ± 2.36 .933
Disease activity (mSLEDAI-2K) at conception, mean ± SD 1.58 ± 2.74 3.16 ± 5.22 .562 1.81 ± 2.98 1.24 ± 2.36 .385 2.16 ± 2.99 1.36 ± 2.64 .222 1.92 ± 3.22 1.20 ± 2.08 .566
Remission, n (%) 45 (63.38) 12 (63.16) .321 25 (59.52) 20 (68.97) .629 10 (52.63) 35 (67.31) .444 23 (62.16) 22 (64.71) .955
Mild, n (%) 19 (26.76) 3 (15.79) 13 (30.95) 6 (20.69) 6 (31.58) 13 (25.00) 10 (27.03) 9 (26.47)
Moderate and high, n (%) 7 (9.86) 4 (21.05) 4 (9.52) 3 (10.34) 3 (15.79) 4 (7.69) 4 (10.81) 3 (8.82)
SDI score at conception, mean ± SD 0.35 ± 0.66 0.58 ± 0.90 .400 0.36 ± 0.62 0.34 ± 0.72 .612 0.21 ± 0.42 0.40 ± 0.72 .463 0.24 ± 0.55 0.47 ± 0.75 .169
Active organ involvement during pregnancy
Renal 30 (42.25) 10 (52.63) .419 23 (54.76) 7 (24.14) .010 13 (68.42) 17 (32.69) .007 24 (64.86) 6 (17.65) <.001
Mucocutaneous 23 (32.39) 4 (21.05) .338 12 (28.57) 11 (37.93) .407 4 (21.05) 19 (36.54) .217 9 (24.32) 14 (41.18) .130
Vasculitis 2 (2.82) 1 (5.26) .513 1 (2.38) 1 (3.45) >.999 1 (5.26) 1 (1.92) .466 1 (2.70) 1 (2.94) >.999
Arthritis 2 (2.82) 0 >.999 2 (4.76) 0 .510 0 2 (3.85) >.999 1 (2.70) 1 (2.94) >.999
Hematologic 8 (11.27) 0 .125 6 (14.29) 2 (6.90) .333 4 (21.05) 4 (7.69) .197 5 (13.51) 3 (8.82) .532
Medication at conception
Prednisolone, n (%) 56 (78.87) 17 (89.47) .294 32 (76.19) 24 (82.76) .505 15 (78.95) 41 (78.85) .993 31 (83.78) 25 (73.53) .290
Dose (in mg/day), mean ± SD 9.11 ± 9.38 16.25 ± 16.58 .058 9.53 ± 9.56 8.54 ± 9.32 .412 12.50 ± 12.32 7.86 ± 7.88 .162 9.11 ± 9.39 9.10 ± 9.57 .823
Prednisolone >10 mg/day 10 (14.08) 6 (31.58) .076 6 (14.29) 4 (13.79) .953 5 (26.32) 5 (9.62) .073 6 (16.22) 4 (11.76) .590
Hydroxychloroquine, n (%) 29 (40.85) 8 (42.11) .921 15 (35.71) 14 (48.28) .290 6 (31.58) 23 (44.23) .337 13 (35.14) 16 (47.06) .307
Dose (in mg/day), mean ± SD 191.38 ± 86.67 256.25 ± 129.39 .144 183.33 ± 79.43 200.00 ± 96.08 .762 166.67 ± 51.64 197.83 ± 93.52 .533 165.38 ± 55.47 212.50 ± 102.47 .275
Immunosuppressive drug† 18 (25.35) 4 (21.05) .699 10 (23.81) 8 (27.59) .719 5 (26.32) 13 (25.00) .910 12 (32.43) 6 (17.65) .153
Mycophenolate mofetil, n (%) 4 (5.63) 0 .575 2 (4.76) 2 (6.90) >.999 1 (5.26) 3 (5.77) >.999 3 (8.11) 1 (2.94) .615
Cyclophosphamide, n (%) 3 (4.23) 3 (15.79) .106 3 (7.14) 0 .265 1 (5.26) 2 (3.85) >.999 3 (8.11) 0 .241
Azathioprine, n (%) 10 (14.08) 0 .083 5 (11.90) 5 (17.24) .525 3 (15.79) 7 (13.46) .803 6 (16.22) 4 (11.76) .590
Cyclosporine, n (%) 2 (2.82) 1 (5.26) .513 0 2 (6.90) .163 0 2 (3.85) >.999 1 (2.70) 1 (2.94) >.999
Flare during pregnancy 32 (45.07) 5 (26.32) .140 23 (54.76) 9 (31.03) .048 11 (57.89) 21 (40.38) .189 22 (59.46) 10 (29.41) .011
Table 3 Comparison of clinical characteristics of adverse maternal outcomes in pregnant SLE patients.
Premature rupture of membrane Pregnancy induced hypertension Flares
Characteristics Yes (n = 10) No (n = 80) P value Yes (n = 8) No (n = 82) P value Yes (n = 37) No (n = 53) P value
Age at pregnancy (in years), mean ± SD 28.85 ± 4.38 26.70 ± 4.82 .182 25.92 ± 3.65 27.03 ± 4.90 .535 26.89 ± 4.75 26.97 ± 4.88 .937
Disease duration prior to conception (in years), mean ± SD 3.81 ± 3.06 5.55 ± 5.31 .521 4.67 ± 6.25 5.43 ± 5.04 .257 5.67 ± 5.45 5.14 ± 4.92 .608
Co-morbidities
Hypertension, n (%) 1 (10.00) 22 (27.50) .232 1 (12.50) 22 (26.83) .375 14 (37.84) 9 (16.98) .026
Diabetes, n (%) 0 1 (1.25) >.999 0 1 (1.22) >.999 0 1 (1.89) >.999
Dyslipidemia, n (%) 0 8 (10.00) .295 0 8 (9.76) .355 3 (8.11) 5 (9.43) .828
APS, n (%) 0 3 (3.75) >.999 0 3 (3.66) >.999 2 (5.41) 1 (1.89) .566
ANA positive, n (%) 10 (100.00) 79 (98.75) >.999 7 (87.50) 82 (100.00) .089 37 (100.00) 52 (98.11) >.999
Anti-dsDNA, n (%)∗ 5/9 (55.56) 45/76 (59.21) .833 5/7 (71.43) 45/78 (57.69) .479 20/35 (57.14) 30/50 (60.00) .792
Anti-Sm, n (%)∗ 0/1 1/11 (9.09) >.999 0/1 1/11 (9.09) >.999 0/4 1/8 (12.50) >.999
ACL/LAC, n (%)∗ 0/4 6/39 (15.38) >.999 0/3 6/40 (15.00) >.999 2/16 (12.50) 4/27 (14.81) >.999
Anti-Ro, n (%)∗ 1/4 (25.00) 20/42 (47.62) .614 2/4 (50.00) 19/42 (45.24) >.999 6/15 (40.00) 15/31 (48.39) .592
Anti-La, n (%)∗ 1/4 (25.00) 19/43 (44.19) .626 2/4 (50.00) 18/43 (41.86) >.999 6/15 (40.00) 14/32 (43.75) .808
Pregnancy loss (ever), n (%) 3 (30.00) 29 (36.25) .697 2 (25.00) 30 (36.59) .513 9 (24.32) 23 (43.40) .063
Cumulative number of ACR criteria, mean ± SD 5.30 ± 1.06 5.51 ± 1.17 0.586 5.62 ± 0.52 5.48 ± 1.20 .518 5.54 ± 1.14 5.45 ± 1.17 .725
Disease activity (mSLEDAI-2K) at -6M, mean ± SD 0.40 ± 1.26 1.89 ± 3.35 .116 0.25 ± 0.71 1.86 ± 3.33 .163 1.70 ± 3.44 1.74 ± 3.09 .696
Disease activity (mSLEDAI-2K) at conception, mean ± SD 0.70 ± 1.34 2.06 ± 3.59 .400 1.00 ± 2.14 2.00 ± 3.54 .454 2.16 ± 3.92 1.74 ± 3.09 .624
Remission, n (%) 7 (70.00) 50 (62.50) 0.450 6 (75.00) 51 (62.20) .704 22 (59.46) 35 (66.04) 0.816
Mild, n (%) 3 (30.00) 19 (23.75) 1 (12.50) 21 (25.61) 10 (27.03) 12 (22.64)
Moderate and high, n (%) 0 11 (13.75) 1 (12.50) 10 (12.20) 5 (13.51) 6 (11.32)
SDI score at conception, mean ± SD 0.50 ± 0.85 0.39 ± 0.70 .728 0 ± 0 0.44 ± 0.74 .079 0.54 ± 0.80 0.30 ± 0.64 .120
Active organ involvement during pregnancy
Renal 6 (60.00) 34 (42.50) .294 5 (62.50) 35 (42.68) .282 27 (72.97) 13 (24.53) <.001
Mucocutaneous 4 (40.00) 23 (28.75) .464 4 (50.00) 23 (28.05) .234 17 (45.95) 10 (18.87) .006
Vasculitis 0 3 (3.75) >.999 0 3 (3.66) >.999 3 (8.11) 0 .066
Arthritis 0 2 (2.50) >.999 0 2 (2.44) >.999 1 (2.70) 1 (1.89) >.999
Hematologic 2 (20.00) 6 (7.50) .190 3 (37.50) 5 (6.10) .003 8 (21.62) 0 <.001
Medication at conception
Prednisolone, n (%) 8 (80.00) 65 (81.25) .924 4 (50.00) 69 (84.15) .039 29 (78.38) 44 (83.02) .580
Dose (in mg/day), mean ± SD 5.94 ± 2.65 11.36 ± 12.78 .423 19.38 ± 27.26 10.27 ± 10.41 .755 8.88 ± 7.89 12.02 ± 13.63 .958
Prednisolone >10 mg/day 0 16 (20.00) .119 1 (12.50) 15 (18.29) .683 5 (13.51) 11 (20.75) .377
Hydroxychloroquine, n (%) 2 (20.00) 35 (43.75) .150 2 (25.00) 35 (42.68) .332 12 (32.43) 25 (47.17) .162
Dose (in mg/day), mean ± SD 125.00 ± 106.07 210.00 ± 98.37 .223 150.00 ± 70.71 208.57 ± 100.36 .382 208.33 ± 129.39 204.00 ± 84.06 .797
Immunosuppressive drug† 2 (20.00) 20 (25.00) .729 0 22 (26.83) .092 7 (18.92) 15 (28.30) .308
Mycophenolate mofetil, n (%) 1 (10.00) 3 (3.75) .381 0 4 (4.88) >.999 2 (5.41) 2 (3.77) >.999
Cyclophosphamide, n (%) 0 6 (7.50) .370 0 6 (7.32) .428 1 (2.70) 5 (9.43) .208
Azathioprine, n (%) 1 (10.00) 9 (11.25) .906 0 10 (12.20) .295 4 (10.81) 6 (11.32) .940
Cyclosporine, n (%) 0 3 (3.75) >.999 0 3 (3.66) >.999 0 3 (5.66) .266
Flare during pregnancy 8 (80.00) 29 (36.25) .008 5 (62.50) 32 (39.02) .198
Factors that might be associated with adverse fetal and maternal outcomes, and those that had a statistical difference with a P value of <.2 in the univariate analysis (Tables 2 and 3) were included in the multiple logistic regression analysis (Tables 4 and 5). Independent predicting factors that increased the risk of fetal loss included age at pregnancy of ≥25 years (AOR [95% CI]) 4.15 [1.10–15.72], P = .036), and ever having renal involvement (9.21 [1.03–82.51], P = .047). Prednisolone used (>10 mg/day) at conception almost reached a predicting factor for fetal loss (3.89 [0.99–15.20], P = .051). Renal involvement during pregnancy independently predicted prematurity (6.02 [1.77–20.52], P = .004), and SGA (4.46 [1.44–13.78], P = .009) and LBW infants (10.01 [3.07–32.62], P < .001). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception independently reduced the risk of prematurity (0.11 [0.02–0.85], P = .034). SLE flares and hematologic involvement during pregnancy independently predicted PROM (8.45 [1.58–45.30], P = .013) and PIH (9.24 [1.70–50.24], P = .010), respectively. Independent predicting factors for SLE flares during pregnancy included the presence of cutaneous vasculitis (AOR [95% CI]) 33.87 [1.05–1094.65], P = .047), and renal (31.89 [6.66–152.69], P < .001), mucocutaneous (9.17 [1.83–45.90], P = .007) and hematologic involvement (128.00 [4.60–3,564.46], P = .004). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception independently reduced the risk of SLE flares during pregnancy (0.08 [0.01–0.68, P = .021).
Table 4 Univariable analysis and multiple logistic regression analysis of factors associated with adverse fetal outcomes in pregnant SLE patients.
Pregnancy loss Prematurity Small for gestational age Low birth weight
Characteristics N1 n OR (95% CI) P value N2 n OR (95% CI) P value n OR (95% CI) P value n OR (95% CI) P value
Age at pregnancy
<25 years 39 4 3.64 35 21 0.93 13 0.34 19 0.84
≥25 years 51 15 (1.01–16.37) .027a 36 21 (0.32–2.67) .886 6 (0.09–1.16) .051 18 (0.30–2.37) .718
Disease duration prior to conception
<5 years 56 8 2.87 48 28 1.11 13 0.95 26 0.78
≥5 years 34 11 (0.90–9.34) .042 23 14 (0.36–3.52) .839 6 (0.25–3.28) .929 11 (0.25–2.36) .617
Hypertension
No 67 12 2.00 55 33 0.86 12 2.79 27 1.73
Yes 23 7 (0.56–6.64) .204 16 9 (0.24–3.15) .788 7 (0.71–10.44) .081 10 (0.48–6.59) .345
Previous pregnancy
0 45 7 1.97 38 21 1.42 11 0.78 21 0.76
≥1 45 12 (0.62–6.61) .196 33 21 (0.49–4.12) .474 8 (0.23–2.56) .655 16 (0.27–2.15) .568
Pregnancy loss (ever)
No 58 10 1.88 48 30 0.65 13 0.95 26 0.78
Yes 32 9 (0.58–5.92) .226 23 12 (0.21–2.03) .408 6 (0.25–3.28) .929 11 (0.25–2.36) .617
Renal disorder (ever)
No 18 1 5.67 17 6 3.67 3 1.96 5 3.49
Yes 72 18 (0.76–249.73) .071b 54 36 (1.02–13.92) .022 16 (0.45–12.00) .330 32 (0.96–14.27) .032
SLE disease activity at conception
Remission and mild 79 15 2.44 64 38 0.91 16 2.25 33 1.25
Moderate and high 11 4 (0.46–11.06) .186 7 4 (0.14–6.76) .909 3 (0.29–14.72) .311 4 (0.19–9.22) .779
Prednisolone >10 mg/day at conception
No 74 13 2.82 61 36 1.04 14 3.36 31 1.45
Yes 16 6 (0.70–10.38) .076c 10 6 (0.22–5.55) .953 5 (0.66–16.66) .073 6 (0.31–7.68) .590
IM drugs used at conception
No 68 15 0.78 53 32 0.82 14 1.07 25 2.24
Yes 22 4 (0.17–2.93) .699 18 10 (0.24–2.83) .719 5 (0.25–3.99) .910 12 (0.65–8.33) .152
Prednisolone >10 mg/day and IM drugs used at conception
No 82 17 1.27 65 40 0.31 17 1.41 34 0.91
Yes 8 2 (0.12–7.98) .778 6 2 (0.03–2.40) .179d 2 (0.12–10.86) .704 3 (0.11–7.33) .914
HCQ used during pregnancy
No 47 11 0.75 36 23 0.67 11 0.67 21 0.60
Yes 43 8 (0.23–2.33) .577 35 19 (0.23–1.93) .410 8 (0.20–2.20) .464 16 (0.21–1.70) .287
Organ involvement during Pregnancy
Cutaneous vasculitis
No 87 18 1.92 69 41 0.68 18 2.83 36 0.92
Yes 3 1 (0.03–38.45) .598 2 1 (0.01–55.50) .789 1 (0.03–226.66) .451 1 (0.01–74.11) .952
Arthritis
No 88 19 0.71 69 40 3.64 19 0.52 36 0.92
Yes 2 0 (0.03–15.47) .829 2 2 (0.17–78.70) .410 0 (0.02–11.28) .676 1 (0.01–74.11) .952
Renal
No 50 9 1.52 41 19 3.80 6 4.46 13 8.62
Yes 40 10 (0.48–4.78) .419 30 23 (1.21–12.72) .010e 13 (1.28–16.62) .007f 24 (2.54–31.31) <.001g
Mucocutaneous
No 63 15 0.56 48 30 0.65 15 0.46 28 0.46
Yes 27 4 (0.12–2.03) .338 23 12 (0.21–2.03) .408 4 (0.10–1.76) .217 9 (0.14–1.42) .130
Hematologic
No 82 19 0.19 63 36 2.25 15 3.20 32 1.61
Yes 8 0 (0.01–3.47) .264 8 6 (0.36–24.23) .333 4 (0.52–19.11) .115 5 (0.28–11.21) .532
Flares during pregnancy
No 53 14 0.44 39 19 2.69 8 2.03 15 3.52
Yes 37 5 (0.11–1.47) .140 32 23 (0.90–8.28) .048 11 (0.62–6.84) .189 22 (1.18–10.70) .011
Table 5 Univariable analysis and multiple logistic regression analysis of factors associated with adverse maternal outcomes in pregnant SLE patients.
Premature rupture of the membrane Pregnancy induced hypertension Flares
Characteristics N n OR 95% CI P value n OR 95% CI P value n OR 95% CI P value
Age at pregnancy
<25 years 39 2 Ref. 4 Ref. 18 Ref.
≥25 years 51 8 3.44 0.62–34.83 .114 4 0.74 0.13–4.31 .690 19 0.69 (0.27–1.76) .395
Disease duration prior to conception
<5 years 56 7 Ref. 6 Ref. 22 Ref.
≥5 years 34 3 0.68 0.10–3.25 .590 2 0.52 0.05–3.17 .435 15 1.22 (0.47–3.15) .652
Hypertension
No 67 9 Ref. 7 Ref. 23 Ref.
Yes 23 1 0.29 0.01–2.36 .232 1 0.39 0.01–3.35 .375 14 2.98 (1.01–8.99) .026
Previous pregnancy
0 45 4 Ref. 4 Ref. 20 Ref.
≥1 45 6 1.58 0.34–8.16 .502 4 1.00 0.17–5.76 >.999 17 0.76 (0.30–1.91) .520
Pregnancy loss (ever)
No 58 7 Ref. 6 Ref. 28 Ref.
Yes 32 3 0.75 0.12–3.63 .697 2 0.58 0.05–3.52 .514 9 0.42 (0.14–1.15) .063
Renal disorder (ever)
No 18 1 Ref. 0 Ref. 5 Ref.
Yes 72 9 2.43 0.30–112.60 .402 8 4.88 0.27–88.50 .284 32 2.08 (0.61–8.19) .199
SLE disease activity at conception
Remission and mild 79 10 Ref. 7 Ref. 32 Ref.
Moderate and high 11 0 0.29 0.02–5.26 .401 1 1.03 0.02–9.54 .980 5 1.22 (0.27–5.27) .755
Prednisolone >10 mg/day at conception
No 74 10 Ref. 7 Ref. 32 Ref.
Yes 16 0 0.19 0.01–3.34 .254 1 0.64 0.01–5.64 .682 5 0.60 (0.15–2.11) .377
IM drugs used at conception
No 68 8 Ref. 8 Ref. 30 Ref.
Yes 22 2 0.75 0.07–4.22 .729 0 0.16 0.01–2.85 .212 7 0.59 (0.18–1.79) .308
Prednisolone >10 mg/day and IM drugs used at conception
No 82 10 Ref. 8 Ref. 36 Ref.
Yes 8 0 0.41 0.02–7.57 .546 0 0.52 0.03–9.74 .659 1 0.18 (0.00–1.55) .085c
HCQ used during pregnancy
No 47 8 Ref. 5 Ref. 20 Ref.
Yes 43 2 0.24 0.02–1.31 .062 3 0.63 0.09–3.50 .542 17 0.88 (0.35–2.22) .771
Organ involvement during pregnancy
Cutaneous vasculitis
No 87 10 Ref. 8 Ref. 34 Ref.
Yes 3 0 1.05 0.05–21.88 .973 0 1.34 0.06–28.11 .852 3 10.86 (0.54–216.71) .119d
Arthritis
No 88 10 Ref. 8 Ref. 36 Ref.
Yes 2 0 1.50 0.07–33.32 .799 0 1.89 0.08–42.79 .688 1 1.44 (0.02–115.53) .796
Renal
No 50 4 Ref. 3 Ref. 10 Ref.
Yes 40 6 2.03 0.44–10.49 .294 5 2.24 0.40–15.24 .282 27 8.31 (2.90–24.34) <.001e
Mucocutaneous
No 63 6 Ref. 4 Ref. 20 Ref.
Yes 27 4 1.65 0.31–7.69 .464 4 2.56 0.43–14.84 .196 17 3.66 (1.29–10.54) .006f
Hematologic
No 82 8 Ref. 5 Ref. 29 Ref.
Yes 8 2 3.08 0.26–21.22 .190 3 9.24 1.07–64.46 .003b 8 30.83 (1.72–553.28) .020g
Flares during pregnancy
No 53 2 Ref. 3 Ref.
Yes 37 8 7.03 1.26–70.80 .008a 5 2.60 0.46–17.73 .198
4 Discussion
Despite significant improvement in medical care for pregnant SLE patients, their APOs are still a significant issue.[5,18] Fetal loss (both spontaneous abortion and intra-uterine death), pre-term birth, intra-uterine growth retardation, SGA and LBW in the fetus, and PIH, pre-eclampsia/eclampsia and flares in the mother are among the major APOs of concern. Reports on SLE patients with APOs varied greatly among studies. This could be explain partly by the difference in time period of the study and ethnicity and socioeconomic status of the patients, as well as SLE disease activity prior to and at the time of conception, organ involvement at conception, rate and organ of flares, and prevalence of ACL/LAC or anti-phospholipid syndrome in the population studied.[1,3,19]
Progressive improvement in pregnancy outcomes over a 25-year period was observed in this study. The proportion of successful pregnancies tended to improve with an increased proportion of full-term births and decreased proportion of pre-term infants. An increased proportion of infants with SGA and LBW had slightly decreased mean fetal birth weight; although all of these changes did not reach statistical significance. The improvement in pregnancy outcomes in Thai SLE patients was similar overtime to that in many previous reports.[5,18,20,21] However, the reason for the increased frequency of SGA and LBW was not clear, despite more frequent full-term birth infants.
This study also found that pregnancy outcomes of subsequent pregnancies in SLE patients showed a slightly decreased proportion of live births, full-term births, and SGA and LBW infants, but with slightly increased proportion of fetal loss, particularly among medical terminations. The lower proportion of SGA and LBW in the subsequent pregnancies in this study was similar to that of Wallanius et al,[22] but different from that of Korese et al,[23] who found that the fetal and maternal outcomes were almost similar between the first and subsequent pregnancies, except for the latter having slightly lower pre-term births. Reasons for the higher proportion of medical terminations in subsequent pregnancies in this study were not clear, but this might have been due to decisions made by the mothers and physicians, who were afraid of severe maternal or fetal complications if the pregnancy continued, and the patients probably had a baby already from the previous pregnancy. The proportion of cesarean section delivery among the subsequent pregnancies in this study was significantly (approximately 2 times) higher than that in the first pregnancy, which was similar to that reported by Wallenius et al.[22] This could be explained by the perception of the patients and physicians in that they were afraid of possible uterine rupture during delivery.
The PIH and eclampsia prevalence of 8.89% and 1.11%, respectively, in this study was in line with many previous reports that showed prevalence of 0–19% and 0–20% for PIH[20,23–27] and pre-eclampsia, respectively[20,23–27]. However, when looking at details, studies with a high incidence of PIH had a rather low incidence of pre-eclampsia or vise-versa; except for that reported by Wu et al,[27] and Kroese et al.[23] The reason for the discordance among these reports was unclear. It is not easy in clinical practice to differentiate between PIH and pre-eclampsia in pregnant patients with pre-existing hypertension and renal disease, as hypertension is an important clinical feature in both conditions. For example, a patient with pre-existing hypertension and some degree of proteinuria has slightly increasing proteinuria (without blood cells or cellular casts in the urine, with decreasing complement level, or increasing anti-dsDNA), and elevated blood pressure in the late course of pregnancy. In this situation, many physicians might consider PIH, while others consider pre-eclampsia. A definite diagnosis of these 2 conditions probably can be made only upon patient follow-up of the patients whether both hypertension and proteinuria are resolved or returned to baseline level prior to the development of hypertension and increasing proteinuria during the post-partum period. There were no pre-eclampsia cases in this study. As patients with increasing hypertension and slightly increasing proteinuria without active urine sediment had their blood pressure, but not the proteinuria, returned to normal or baseline during the post-partum period. These patients were considered to have PIH and not pre-eclampsia.
Similar to the differentiation between PIH and pre-eclampsia, differentiation between pre-eclampsia and active nephritis flare is another challenging issue in clinical practice. Several reviews suggest that the presence of extra-renal manifestation, past history of lupus nephritis, presence of or increasing proteinuria at the early trimester of pregnancy, presence of new hypertension onset, presence of active urinary sediments, decreasing serum complement levels, increasing anti-dsDNA levels and normal serum uric acid, favor active nephritis. However, if the aforementioned conditions occur late in the pregnancy, and the patient does not have decreasing complement or increasing anti-dsDNA levels, differential diagnosis between active nephritis and pre-eclampsia would be more difficult.[28–30] The situation would be more complicated if the patient has underlying hypertension prior to pregnancy or slight proteinuria prior to conception. Furthermore, these 2 conditions can co-exist in the same patients.[31] Some authors have suggested performing a kidney biopsy in the latter condition,[29,32] as the management of active lupus nephritis and pre-eclampsia is different. Again, sometimes the diagnosis can be made only upon delivery of the fetus when the above conditions disappear or return to normal.[3] All of the patients who had significantly increasing proteinuria in this study also had active urine sediment, and the degree of proteinuria did not return to normal or baseline at the end of the post-partum period. All of them also showed renal response to an increasing dose of corticosteroid and immunosuppressive drugs, therefore, they were more likely to have active nephritis flare rather than pre-eclampsia.
The pathogenic mechanisms of PIH and pre-eclampsia are not clear, but have been reviewed widely, and included innate immunity,[33] bioactive factors (such as inflammatory cytokines, angiogenetic factors, growth factors, etc.),[34,35] oxidative stress,[36] placental vascular maladaptation,[37] and endothelial dysfunction.[38,39] Among these, endothelial dysfunction is the most likely underlying mechanism,[39] which causes imbalance between an endothelial-derived vasodilator (such as nitric oxide and prostacyclin) and vasoconstrictors (such as endothelin-1, thromboxane A2), leading to the promotion of vasoconstriction, hypertension, and pre-eclampsia. Placenta ischemia stimulates the release of several bioactive factors and inflammatory cytokines that target the endothelial cells that lead to generalized endothelial cell dysfunction, which in turn causes vascular remodeling, increased arterial stiffness, and hypertension. Current treatment options of pre-eclampsia are limited. Only low dose aspirin has been shown as effective and is recommended by several international obstetrics and gynecologists guidelines for use in preventing pre-eclampsia in high risk patients.[40] Unfortunately, the effect of low dose aspirin on pregnancy outcomes was not determined in this study.
The effect of HCQ use on pregnancy outcomes also has been of interest in lupus pregnancy, although many previous studies could not find a significant difference in overall SLE pregnancy outcomes between HCQ users and non-users.[41–43] However, some studies showed some beneficial effects of HCQ use during pregnancy, including lower rate of fetal loss and pre-term births,[20,44] intra-uterine growth restriction (IUGR) in the fetus,[44] longer duration of pregnancy,[42] flare prevention,[43,45] and decreased PIH.[46] Although no significant difference in APOs among HCQ users and non-users was demonstrated in this study, there tended to be fewer maternal complications among HCQ users, particularly in a lower proportion of PROM, PIH and SLE flares.
Several factors have been identified in association with APOs in pregnant patients with SLE. These have included the presence of renal involvement or active nephritis,[20,24,47–53] SLE flares during pregnancy,[7,24,50,53,54] active disease prior to or during pregnancy,[20,50,54–56] hypertension,[7,24,25,54–57] presence of anti-phospholipid antibodies (APL) and/or lupus anti-coagulants,[7,20,23,24,50,53,54,56,57] cytopenia,[41,50,52,54] and hypocomplementemia.[20,25,50,54,56,58,59] This study also confirmed that renal involvement during pregnancy was associated with poor pregnancy outcomes, in both the fetus and mother. However, the presence of hypertension only associated with maternal flares.
Although APOs have been reported in several studies, only a few identified independent predicting factors for adverse fetal and maternal outcomes. In addition, the results of these predicting factors also were inconsistent. For example, Cortes-Hernandez et al[25] found that the presence of ACL and hypertension during pregnancy were independent predicting factors for poor fetal outcomes, whereas the presence of anti-β2-glycoprotein-1, hypertension at conception and hypocomplemetemia were independent predicting factors for fetal loss. Kwok et al[24] found that hypertension was an independent predicting factor for fetal loss, nephritis for SGA, low serum albumin for IUGR and SLE flares for prematurity among infants; and nephritis was an independent predicting factor for SLE flares, and hypertension and high disease activity for pre-eclampsia among mothers. Ko et al[26] found that the presence of APL antibodies was an independent predicting factor for fetal loss and pre-term births, and active disease for pre-term births. Active SLE and SLE flares were independent predicting factors for PIH and IUGR among mothers. Buyon et al[41] found that the presence of LAC, hypertension, high disease activity, maternal flares, and thrombocytopenia were predictors of APOs. Lui et al[60] found that pre-eclampsia/eclampsia and thrombocytopenia were independent predicting factors for fetal loss and SLE flares in mothers. Pre-eclampsia/eclampsia also was an independent predicting factor for pre-term birth among infants. Borella et al[56] found that hypertension was an independent predicting factor for fetal loss, miscarriage and SGA, and anti-phospholipid syndrome (APS) for prematurity in infants; whereas LAC was an independent predicting factor for pre-eclampsia, and active disease at −6 M for PROM. Kalok et al[6] found that SLE flares and active disease were predicting factors for fetal loss and pre-term birth, and also SLE flares for SGA among infants. Active SLE was an independent predicting factor for SLE flares and lupus nephritis, while SLE flares and the presence of APL antibodies were independent predicting factors for pre-eclampsia among mothers. Wu et al[59] recently found that unplanned pregnancy, hypocomplementemia and urine protein >1.0 gm/day were independent predicting factors for fetal loss. This study found that age >25 years and ever having renal involvement were independent predicting factors for fetal loss, renal involvement during pregnancy, prematurity, SGA and LBW among infants. SLE flare during pregnancy and hematologic involvement were independent predicting factors for PROM and PIH, respectively, among mothers. It was interesting that the use of prednisolone (>10 mg/day) and immunosuppressive drugs at conception was an independent protecting factor for prematurity. The presence of cutaneous vasculitis, and renal, mucocutaneous and hematologic involvement during pregnancy was an independent predicting factor for SLE flares; while the use of prednisolone (>10 mg/day) and immunosuppressive drugs at the time of conception reduced the risk of SLE flares independently. The predicting factors identified from this study were similar to many of those mentioned in the aforementioned studies. However, this study could not demonstrate that the presence of ACL/LAC was an independent factor for poor pregnancy outcomes. This might relate to the small number of patients with poor pregnancy outcome, who were among those with a positive test for these antibodies, as previously discussed. A larger study, including more patients with APL/LAC, needs to be carried out in order to verify this association in Thai patients.
The use of mSLEDAI-2K, the modified SFI and modified SLE disease activity severity score would have caused a limitation in this study. The SLE disease activity or flares would be underestimated (as the score for anti-dsDNA and complement would not be counted), making it difficult to compare this study with those that used scores from the original version. However, the mSLEDAI-2K has been shown to correlate very well (r = 0.924) with the original SLEDAI-2K.[13] In addition, use of the mSLEDAI-2K score in this study reflects real world practice, as many institutions could not perform anti-dsDNA and complements routinely. The small number of patients with positive ACL/LAC did not demonstrate the effect of these antibodies on APOs clearly. However, all of the patients in this study were taken care of by the same group of rheumatologists, who collectively made more uniformed therapeutic decisions, which should add more strength to the outcomes.
5 Conclusion
This study showed that pregnancy outcomes in Thai patients with SLE has improved over a 25-year period. However, a significant number of APOs were still observed. Renal involvement and flares during pregnancy were associated with both poor fetal and maternal outcomes. The beneficial effect of HCQ in lupus pregnancy was not demonstrated clearly, but there was a trend in favor of better pregnancy outcomes among the HCQ users. Age ≥ 25 years at conception, the presence of or ever having renal involvement during pregnancy, presence of SLE flare and hematologic involvement during pregnancy were predicting factors for poor pregnancy outcomes. Cutaneous vasculitis, and renal, hematologic and mucocutaneous involvement during pregnancy predicted SLE flare. The effect of APL/LAC on pregnancy outcomes in Thai populations needs further investigations.
Acknowledgments
The authors thank Mrs. Waraporn Sukitawut, Ms. Saowanee Pantana and Ms. Phimwalan Konkaeo for their secretarial assistance.
Author contributions
Conceptualization: Worawit Louthrenoo, Thananant Trongkamolthum, Nuntana Kasitanon, Antika Wongthanee.
Data curation: Worawit Louthrenoo, Thananant Trongkamolthum.
Formal analysis: Worawit Louthrenoo, Antika Wongthanee.
Investigation: Worawit Louthrenoo, Thananant Trongkamolthum.
Methodology: Worawit Louthrenoo, Thananant Trongkamolthum.
Supervision: Worawit Louthrenoo.
Validation: Worawit Louthrenoo, Antika Wongthanee.
Visualization: Worawit Louthrenoo, Antika Wongthanee.
Writing – original draft: Worawit Louthrenoo, Thananant Trongkamolthum.
Writing – review & editing: Worawit Louthrenoo, Thananant Trongkamolthum, Nuntana Kasitanon, Antika Wongthanee.
Abbreviations: 95% CI = 95% confidence intervals, ACL = anti-cardiolipin antibodies, ACR = American College of Rheumatology, ANA = antinuclear antibodies, Anti-dsDNA = anti-double stranded DNA antibodies, Anti-Ro = anti-Ro antibodies, Anti-Sm = anti-Smith antibodies, AOR = adjusted odds ratio, APL = anti-phospholipid antibodies, APO = adverse pregnancy outcomes, APS = anti-phospholipid syndrome, HCQ = hydroxychloroquine, HELLP syndrome = hemolysis, elevated liver enzymes, and low platelet count syndrome, IM drugs = immunosuppressive drugs, LAC = lupus coagulants, LBW = low birth weight, mSLEDAI-2K = modified Systemic Lupus Erythematosus Disease Activity Index-2000, OR = odds ratio, PGA = physician global assessment, PIH = pregnancy induced hypertension, PPH = post-partum hemorrhage, PROM = premature rupture of membrane, SDI = the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, SFI = the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE flare index, SGA = small for gestational age, SLE = systemic lupus erythematosus, VLBW = very low birth weight.
How to cite this article: Louthrenoo W, Trongkamolthum T, Kasitanon N, Wongthanee A. Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus: a STROBE-compliant study. Medicine. 2021;100:5(e24553).
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
∗ twin pregnancy.
† maternal complications (PROM + oligohydramnios = 1, PROM + post-partum hemorrhage = 1, PROM + PIH = 1, PIH + eclampsia = 1), ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, LBW = low birth weight, PIH = pregnancy induced hypertension, PPH = post-partum hemorrhage, PROM = premature rupture of membrane, SGA = small for gestational age.
∗ number of positive tests/number tested.
† excluding hydroxychloroquine, −6 M = 6 months prior to conception, ACR = American College of Rheumatology, ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, APS = anti-phospholipid syndrome, BW = birth weight, LBW = low birth weight, SDI = Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index, mSLEDAI-2K = modified systemic lupus erythematosus disease activity index – 2000, SGA = small for gestational age.
∗ number of positive tests/number tested.
† excluding hydroxychloroquine, −6 M = 6 months prior to conception, ACR = American College of Rheumatology, ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, APS = anti-phospholipid syndrome, SDI = Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index, SLEDAI-2K = systemic lupus erythematosus disease activity index – 2000.
a AOR (95% CI) = 4.15 (1.10–15.72), P = .036.
b AOR (95% CI) = 9.21 (1.03–82.51), P = .047.
c AOR (95% CI) = 3.89 (0.99–15.20), P = .051.
d AOR (95% CI) = 0.11 (0.02–0.85), P = .034.
e AOR (95% CI) = 6.0 (1.77–20.52), P = .004.
f AOR (95% CI) = 4.46 (1.44–13.78), P = .009.
g AOR (95% CI) = 10.01 (3.07–32.62), P < .001.
HCQ = hydroxychloroquine, IM drugs = immunosuppressive drugs, excluding HCQ, n = number of pregnancies with positive conditions, N1 = number of pregnancies, N2 = number of pregnancies with live births.
a AOR (95% CI) = 8.45 (1.58–45.30), P = .013.
b AOR (95% CI) = 9.24 (1.70–50.24), P = .010.
c AOR (95% CI) = 0.08 (0.01–0.68), P = .021.
d AOR (95% CI) = 33.87 (1.05–1,094.65), P = .047.
e AOR (95% CI) = 31.89 (6.66–152.69), P < .001.
f AOR (95% CI) = 9.17 (1.83–45.90), P = .007.
g AOR (95% CI) = 128.00 (4.60–3564.46), P = .004.
HCQ = hydroxychloroquine, IM drugs = immunosuppressive drugs, excluded HCQ, n = number of pregnancies with positive conditions, N1 = number of pregnancies, N2 = number of pregnancies with live birth. | MYCOPHENOLATE MOFETIL | DrugsGivenReaction | CC BY-NC | 33592909 | 19,221,827 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Foetal exposure during pregnancy'. | Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus: A STROBE-compliant study.
Studies on predicting factors for adverse pregnancy outcomes (APOs) in Thai patients with systemic lupus erythematosus (SLE) are limited. This retrospective observation study determined APOs and their predictors in Thai patients with SLE.Medical records of pregnant SLE patients in a lupus cohort, seen from January 1993 to June 2017, were reviewed.Ninety pregnancies (1 twin pregnancy) from 77 patients were identified. The mean age at conception was 26.94 ± 4.80 years. At conception, 33 patients (36.67%) had active disease, 23 (25.56%) hypertension, 20 (22.22%) renal involvement, and 6 of 43 (13.95%) positive anti-cardiolipin antibodies or lupus anti-coagulants, and 37 (41.11%) received hydroxychloroquine. Nineteen patients (21.11%) had pregnancy loss. Of 71 successful pregnancies, 28 (31.11%) infants were full-term, 42 (46.67%) pre-term and 1 (11.11%) post-term; 19 (26.39%) were small for gestational age (SGA), and 38 (52.58%) had low birth weight (LBW). Maternal complications occurred in 21 (23.33%) pregnancies [10 (11.11%) premature rupture of membrane (PROM), 8 (8.89%) pregnancy induced hypertension (PIH), 4 (4.44%) oligohydramnios, 2 (2.22%) post-partum hemorrhage, and 1 (1.11%) eclampsia]. Patients aged ≥ 25 years at pregnancy and those ever having renal involvement had predicted pregnancy loss with adjusted odds ratio (AOR) [95% CI] of 4.15 [1.10-15.72], P = .036 and 9.21 [1.03-82.51], P = .047, respectively. Renal involvement predicted prematurity (6.02 [1.77-20.52, P = .004), SGA (4.46 [1.44-13.78], P = .009), and LBW in infants (10.01 [3.07-32.62], P < .001). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception protected against prematurity (0.11 [0.02-0.85], P = .034). Flares and hematologic involvement predicted PROM (8.45 [1.58-45.30], P = .013) and PIH (9.24 [1.70-50.24], P = .010), respectively. Cutaneous vasculitis (33.87 [1.05-1,094.65], P = .047), and renal (31.89 [6.66-152.69], P < .001), mucocutaneous (9.17 [1.83-45.90], P = .007) and hematologic involvement (128.00 [4.60-3,564.46], P = .004) during pregnancy predicted flare; while prednisolone (>10 mg/day) and immunosuppressive drug use at conception reduced that risk (0.08 [0.01-0.68, P = .021).APOs remain a problem in Thai pregnant SLE patients. Renal involvement and SLE flares were associated with the risk of APOs.
1 Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ systems, characterized by remission and relapse. The disease predominantly affects women of child bearing age. Pregnancy in SLE patients is a challenging issue in clinical practice because of its association with increasing adverse outcomes in both mother and fetus.[1,2] Pregnant women with SLE have a reportedly higher rate of spontaneous abortion, fetal loss, intra-uterine growth retardation, pre-term delivery, pregnancy induced hypertension (PIH), pre-eclampsia and flares. Furthermore, pregnancy in SLE patients can cause disease exacerbation or flare, which often requires increasing doses of corticosteroids and/or immunosuppressive drugs that can have adverse effects on mother and fetus.[3,4] Thus, it is suggested that pregnancy in SLE patients should be avoided if the patients have had active severe disease within the previous 6 months, or significant heart, lung, renal and central nervous system involvement.[3,4]
With progress made in understanding the clinical course of SLE, standard instruments that determine disease activity and flares have been developed, as well as progression in medical treatment that results in improved obstetrics care of pregnant SLE patients.[3,5] Pregnancy outcomes in SLE patients have been reported widely, however, data on pregnancy outcomes from Asian countries are very limited.[6–11]
The purpose of this study was to determine pregnancy outcomes and identify independent predicting factors for adverse pregnancy outcomes (APOs) from a lupus cohort of Thai pregnant patients with SLE.
2 Patients and methods
2.1 Patients and data source
The medical records of SLE patients in a lupus cohort seen between January 1993 and June 2017 at the Division of Rheumatology, Faculty of Medicine, Chiang Mai University, Thailand were reviewed. SLE was diagnosed according to the 1997 updating the American College of Rheumatology (ACR) revised criteria for the classification of SLE.[12] Pregnant SLE patients were identified. Clinical manifestations, laboratory investigations, treatment, and SLE disease activity were recorded from 6 months prior to conception (−6 M) until 6 weeks after termination of pregnancy or delivery or the post-partum period. Pregnancy data were recorded at the time of conception or when the pregnancy was documented. The data were captured at −6 M, 3 months prior to conception (−3 M), at the time of conception, 1st trimester, 2nd trimester, 3rd trimester, and the post-partum period. If the patients had more than 1 visit during each period, the mean SLE disease activity of each period was used for statistical analysis. Laboratory investigations, including complete blood counts, urine analysis, and renal and liver functions were recorded routinely. The 24-hour urine protein creatinine ratio (24hour UPCI) [urine protein in gm/day to urine creatinine in gm/day] was determined only in cases with lupus nephritis (urine protein >0.5 gm/day). SLE patients were followed up usually in the clinic at 1 to 3 month intervals, depending on SLE disease activity or other clinical encounters. If the patients had more than 1 pregnancy, each one was considered as a separate observation and counted as an individual case.
Patients in the clinic should have been in clinical remission or have stable low disease activity (prednisolone ≤10 mg/day without immunosuppressive drugs other than anti-malarial medication) for a minimum of 12 months to allow for pregnancy to occur. Those who developed mild to moderate flares during pregnancy were administered prednisolone at a dosage of up to 0.50 mg/kg/day, and those with severe flares received >0.50 to 1.00 mg/kg/day. Anti-malarial medication was given according to clinical indications, e.g., skin rashes, oral ulcers or alopecia. Immunosuppressive drugs, particularly azathioprine and cyclosporine, were given to cases of severe flares. Cases in which the patients received methotrexate, cyclophosphamide or mycophenolate mofetil at the time of pregnancy, had these immunosuppressive drugs discontinued immediately and replaced with azathioprine or cyclosporine.
2.2 SLE disease activity and flare assessment
The modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K)[13] was used in this study to determine SLE disease activity (as anti-dsDNA and complements were not routinely available at this institution). The severity of SLE disease activity was classified according to that of Abrahamowicz et al,[14] but the mSLEDAI-2K instrument was used instead of the original SLEDAI-2K; remission [mSLEDAI-2K = 0], mild disease activity [mSLEDAI-2K = 1–5], moderate disease activity [mSLEDAI-2K = 6–10], high disease activity [mSLEDAI-2K = 11–19] and very high disease activity [mSLEDAI-2K = ≥20]). The severity of SLE flare (mild or moderate flare and severe flare) followed the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE flare index (SFI).[15] As the physician global assessment (PGA) was not recorded routinely, the SFI was modified by excluding the PGA items (mSFI). Organ damage accrual was determined using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).[16]
2.3 Pregnancy outcomes
The definition of maternal complications (premature rupture of membrane [PROM], oligohydramnios, pregnancy induced hypertension [PIH], pre-eclampsia, eclampsia, and direct and indirect maternal death), and fetal outcomes (pregnancy loss, miscarriage or spontaneous abortion, intra-uterine fetal death, medical termination of pregnancy, pre-term delivery, term delivery, post-term delivery, neonatal death, small for gestational age [SGA], and infant birth weight) followed that of standard references.[17]
2.4 Ethical statement
This study was performed in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This study was approved by the Ethic Committee of the Faculty of Medicine, Chiang Mai University (no. 215/2017).
2.5 Statistical analysis
STATA 14.2 computer software (Stata Corporation, Texas USA) was used for data processing and statistical analysis. As some patients had more than 1 pregnancy, each one was considered individually for statistical analysis. Continuous variables were presented as mean ± standard deviation (SD) or median (min-max), with categorical variables presented as percent. The Student t test and Wilcoxon rank sum test were used to determine the differences between 2 independent samples of continuous variables. One-way analysis of variance (ANOVA) and the Kruskal–Wallis test were used for more than 2 samples, with normal and non-normal distribution, respectively. The Chi-Squared test or Fisher exact test was used to determine associations among the categorical variables, where appropriate. Firth's logistic regression was used to predict the odds ratio (OR) and 95% confidence intervals (95% CI) when the outcome contained cell counts of zero. Variables with a P value <.20 from univariate analysis were entered into multiple logistic regression analysis, and reported as adjusted odds ratio (AOR) and 95% CI. A P ≤ .05 was considered as being a statistically significant difference.
3 Results
3.1 Demographics and characteristics of pregnant SLE patients
From a cohort of 1167 female SLE patients, 90 pregnancies occurred from 77 patients (1, 2, and 3 pregnancies in 66, 9 and 2 patients, respectively). Their mean age at SLE onset and age at pregnancy was 21.63 ± 5.89 years and 26.94 ± 4.80 years, respectively. Pregnancies occurred at the time of SLE diagnosis, and < 5 years and ≥ 5 years after SLE diagnosis in 7 (7.78%), 49 (54.44%) and 34 (37.78%) pregnancies, respectively. Of the 90 pregnancies, 45 (50.00%), 25 (27.78%), and 20 (22.22%) were the first, second and third or more, respectively. Their mean cumulative ACR classification criteria and SDI score were 5.49 ± 1.15 and 0.40 ± 0.72, respectively. The mean ± SD mSLEDAI-2K score at −6 M and time of conception was 1.72 ± 3.22 and 1.90 ± 3.44, respectively. Active disease at the time of conception (mSLEDAI-2K score ≥ 0) was observed in 33 of 90 pregnancies (36.67%), and all of them were unplanned. Active organ involvement at the time of conception was renal (urine protein creatinine ratio >0.5) in 20 (22.22%) pregnancies, mucocutaneous lesions in 15 (16.67%), cutaneous vasculitis in 2 (2.22%), and arthritis and hematologic abnormalities in 1 (1.11%) of each.
Co-morbidities were seen as follows: hypertension in 23 (25.56%) pregnancies, dyslipidemia in 8 (8.89%), thalassemia in 7 (7.78%), anti-phospholipid syndrome in 3 (3.33%), diabetes mellitus in 1 (1.11%), and others in 19 (21.11%) [hepatitis C virus infection, avascular necrosis of the hip, stroke and atrial secundum defect, and past history of cryptococcal meningitis, pneumocystis jirovecii pneumonia, and past treatment of pulmonary tuberculosis]. None of the patients drank alcohol or smoked.
Antinuclear antibodies (ANA) were observed in 89 pregnancies (98.89%). Anti-double stranded DNA (anti-dsDNA), anti-Smith (anti-Sm), anti-cardiolipin (ACL), lupus coagulants (LAC), and anti-Ro (anti-Ro) antibodies were observed in 50 of 85 (58.82%), 1 of 12 (8.33%), 4 of 58 (6.89%), 3 of 42 (7.14%), and 21 of 46 (45.65%) pregnancies that had been tested, respectively.
Patients in 15 of the 90 pregnancies (16.67%) had not received any specific SLE medication at the time of conception. Patients in 57 (63.33%) of the pregnancies received prednisolone at a dose of ≤10 mg/day, and in 16 (17.78%) at ≥ 10 mg/day, with the mean dosage of 10.77 ± 11.73 mg/day. Patients also received hydroxychloroquine (HCQ) in 37 (41.11%) pregnancies, cyclophosphamide in 6 (6.67%), mycophenolate mofetil in 4 (4.40%), azathioprine in 10 (11.11%), and cyclosporine in 3 (3.33%). Both cyclophosphamide and mycophenolate mofetil were switched to azathioprine or cyclosporine when the pregnancy was documented.
3.2 Overall pregnancy outcomes
Of the 90 pregnancies, 19 (21.11%) were lost (spontaneous abortion in 12 (13.33%) [7 in the 1st trimester and 5 in the 2nd], medical termination in 5 (5.56%) [1 in the 1st trimester and 4 in the 2nd], and dead fetus in the utero (1 in each 2nd and 3rd trimester). Of the 71 (78.89%) successful pregnancies, 28 (31.11%) were full-term, 42 (46.67%) pre-term (1 twin pregnancy), and 1 (1.11%) was a post-term delivery, resulting in 72 live born infants. Mode of delivery among the live births were vaginal in 52 (73.24%) and cesarean section in 19 (26.76%). The mean ± SD duration of pregnancy with live born infants was 35.76 ± 3.58 weeks. The mean ± SD weight of the 72 live born infants was 2,367.33 ± 640.30 gm (range 720–3853 gm), with normal birth weight (≥2500 gm), low birth weight (LBW) [1500–2499 gm], and very low birth weight (VLBW) [<1500 gm] in 34 (47.22%), 30 (41.67%) and 8 (11.11%) infants, respectively. SGA infants occurred in 19 live born infants (26.39%). There was 1 neonatal death (1.11%). No infants had congenital anomalies or completed heart block.
Maternal complications occurred in 21 (23.33%) pregnancies. PROM occurred in 10 (11.11%) pregnancies, PIH in 8 (8.89%), oligohydramnios in 4 (4.44%), post-partum hemorrhage in 2 (2.22%), and eclampsia in 1 (1.11%). One concomitant PROM and oligohydramnios, PROM and post-partum hemorrhage, PROM and PIH, and PIH and eclampsia occurred in each pregnancy. There were no cases of anti-partum hemorrhage, post-partum endometritis, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), pre-eclampsia or maternal death. Thirty seven flares (41.11%) were mild to moderate and severe in 9 (24.32%) and 28 (75.68%) pregnancies, respectively.
3.3 Effect of renal involvement, hypertension, presence of anti-cardiolipin antibodies and/or lupus anti-coagulants and SLE flares on pregnancy outcomes
The effects of renal involvement, hypertension, and the presence of ACL/LAC and SLE flares on pregnancy outcomes were determined and are shown in Table 1.
Table 1 Effect of active renal involvement during pregnancy, hypertension at the time of conception, presence of anti-phospholipid antibodies and SLE flares during pregnancy on pregnancy outcomes.
Renal involvement Hypertension ACL/LAC Flares
Yes No P value Yes No P value Yes No P value Yes No P value
Successful pregnancy, n (%) 30 (75.00) 41 (82.00) .419 16 (69.57) 55 (82.09) .204 4 (66.67) 32 (86.49) .248 32 (86.49) 39 (73.58) .140
Pregnancy duration, in weeks, mean ± SD 34.34 ± 4.50 36.80 ± 2.26 .009 35.60 ± 2.47 35.81 ± 3.86 .838 38.50 ± 2.52 36.20 ± 3.45 .209 34.43 ± 3.91 36.85 ± 2.90 .004
Fetal weight, in grams, mean ± SD 2,029.52 ± 611.82 2,622.76 ± 540.06 <.001 2,147.65 ± 580.34 2,435.24 ± 647.59 .106 2,680.00 ± 557.32 2,379.94 ± 749.66 .447 2097.58 ± 615.13 2595.59 ± 575.07 .001
Fetal outcomes
Live birth, n (%) 31 (75.61)∗ 41 (82.00) .456 17 (70.83)∗ 55 (82.09) .244 4 (66.67) 32 (86.49) .248 33 (86.84)∗ 39 (73.58) .125
Term, n (%) 6 (15.00) 22 (44.00) .003 7 (30.43) 21 (31.34) .935 3 (50.00) 14 (37.84) .666 9 (24.32) 19 (35.85) .245
Pre-term, n (%) 24 (58.54)∗ 19 (38.00) .051 10 (41.67)∗ 33 (49.25) .523 1 (16.67) 17 (45.95) .177 24 (63.16)∗ 19 (35.85) .010
Post-term, n (%) 1 (2.50) 0 .444 0 1 (1.49) >.999 0 1 (2.70) >.999 0 1 (1.89) >.999
Total fetal loss, n (%) 10 (25.00) 9 (18.00) .419 7 (30.43) 12 (17.91) .204 2 (33.33) 5 (13.51) .248 5 (13.51) 14 (26.42) .140
Spontaneous abortion, n (%) 6 (15.00) 6 (12.00) .677 4 (17.39) 8 (11.94) .507 1 (16.67) 4 (10.81) .547 3 (8.11) 9 (16.98) .223
Medical termination, n (%) 2 (5.00) 3 (6.00) >.999 2 (8.70) 3 (4.48) .599 1 (16.67) 1 (2.70) .262 1 (2.70) 4 (7.55) .645
Dead fetus in the utero, n (%) 2 (5.00) 0 .195 1 (4.35) 1 (1.49) .448 0 0 1 (2.70) 1 (1.89) >.999
Neonatal death, n (%) 1 (2.50) 0 .444 1 (4.35) 0 .256 0 1 (2.70) >.999 1 (2.70) 0 .411
SGA, n (%) 13 (32.50) 6 (12.00) .018 7 (30.43) 12 (17.91) .204 1 (16.67) 12 (32.43) .649 11 (29.73) 8 (15.09) .094
LBW (< 2500 grams), n (%) 25 (60.98)∗ 13 (26.00) .001 11 (45.83)∗ 27 (40.30) .637 1 (16.67) 18 (48.65) .143 23 (60.53)∗ 15 (28.30) .002
Maternal complications†, n (%) 30 (75.00) 15 (30.00) <.001 16 (69.57) 29 (43.28) .030 2 (33.33) 18 (48.65) .669 37 (100.00) 8 (15.09) <.001
PROM, n (%) 6 (15.00) 4 (8.00) .294 1 (4.35) 9 (13.43) .232 0 4 (10.81) >.999 8 (21.62) 2 (3.77) .008
Oligohydramnios, n (%) 3 (7.50) 1 (2.00) .319 1 (4.35) 3 (4.48) >.999 0 2 (5.41) >.999 2 (5.41) 2 (3.77) >.999
PPH, n (%) 0 2 (4.00) .501 0 2 (2.99) >.999 0 1 (2.70) >.999 0 2 (3.77) .510
PIH, n (%) 5 (12.50) 3 (6.00) .282 1 (4.35) 7 (10.45) .375 0 3 (8.11) >.999 5 (13.51) 3 (5.66) .198
Eclampsia, n (%) 0 1 (2.00) >.999 0 1 (1.49) >.999 0 1 (2.70) >.999 0 1 (1.89) >.999
Flares, n (%) 27 (67.50) 10 (20.00) <.001 14 (60.87) 23 (34.33) .026 2 (33.33) 14 (37.84) >.999
Forty pregnancies were shown to have active nephritis during pregnancy. Active renal involvement occurred in 30, 30, and 26 pregnancies during the 1st, 2nd, and 3rd trimester, respectively, which was significantly higher than the 20 pregnancies seen at the time of conception (P < .001). When compared to patients without renal involvement during pregnancy, those with it had significantly shorter mean pregnancy duration (34.34 ± 4.40 weeks vs 36.80 ± 2.26 weeks, P = .003), lower fetal birth weight among live births (2029.52 ± 611.82 gm vs 2622.76 ± 540.06 gm, P < .001), and a higher proportion of LBW infants (60.98% vs 26.00%, P < .001), and SGA infants (32.50% vs 12.00%, P = .018). Although the proportion among live birth infants was not different, those with renal involvement had a significantly lower proportion of full-term infants (15.00% vs 44.00%, P = .003) and almost significantly higher proportion of pre-term infants (58.54% vs 38.00%, P = .051). There was no statistically significant difference in fetal loss among the 2 groups. The maternal complications in those with renal involvement during pregnancy were significantly higher (75.00% vs 30.00%, P < .001), which was due to a higher proportion of patients with SLE flare (67.50% vs 20.00%, P < .001). Other maternal complications, including PROM, oligohydramnios and PIH, also were higher proportionally, but they did not reach statistical significance.
Overall, there were no statistically significant differences in adverse fetal outcomes among patients with or without hypertension during pregnancy. However, pregnancy outcomes among patients with hypertension tended to have a lower proportion of live birth infants, and higher proportion of fetal loss (both spontaneous and medical terminations), SGA and LBW among full-term infants, and a lower mean fetal birth weight. Maternal complications were significantly higher in patients with hypertension (69.57% vs 43.28%, P = .030), which was due mainly to the higher proportion of those with SLE flares (60.48% vs 34.33%, P = .026). It was interesting that the proportion of PROM and PIH was lower in patients with hypertension, but with no significance.
The effect of anti-cardiolipin antibodies (ACL) and lupus anticoagulant (LAC) tests on pregnancy outcomes also was determined. Unfortunately, these 2 tests were determined in only approximately 50% of the patients. ACA and LAC were positive in a small proportion of the patients (4 of 58 or 6.89% and 3 of 42 or 7.14% of those tested, respectively). Overall, there was no statistically significant difference between either the fetal and maternal outcomes among pregnant patients with positive ACL/LAC or those without; however, those with positive ACL/LAC tended to have a lower proportion of live births and full-term birth infants, and higher proportion of fetal losses. It was interesting that the proportion of SGA, LBW, and maternal complication in the ACL/LAC positive patients also was lower, but without statistical significance. This might be due to the small number of patients in this group.
The effect of flares on pregnancy outcomes also was determined. When compared to SLE patients without flares during pregnancy, those with them had significantly shorter duration of pregnancy (34.43 ± 3.91 weeks vs 36.85 ± 2.90 weeks, P = .004), and lower mean fetal weight among live births (2097.58 ± 615.13 gm vs 2595.59 ± 575.07 gm, P = .001). Although the proportion of live birth infants and fetal loss was no different between the 2 groups, the patients with flares had a significantly higher proportion of pre-term births and LBW infants (63.16% vs 35.85%, P = .010, and 60.53% vs 28.30%, P = .002, respectively). The proportion of SGA infants also was higher, but did not reach statistical significance (29.73% vs 15.09%, P = .094). The adverse maternal outcomes were higher (100.00% vs 15.09%, P < .001), particularly of PROM (21.62% vs 3.77%, P < .008).
3.4 Effect of HCQ used on pregnancy outcomes
The effect of HCQ used during pregnancy on pregnancy outcomes was determined. Overall, there was no statistically significant difference in fetal outcomes among patients who did or did not receive HCQ during pregnancy. However, infants born to mothers who used HCQ tended to have a higher proportion of full term births (37.84% vs 26.42%, P = .249), and lower proportion of SGA (16.22% vs. 24.53%, P = .342) and LBW (36.84% vs 45.28%, P = .421). The proportion of live birth infants and fetal loss was similar between the 2 groups (78.95% vs 79.25%, P = .972, and 21.62% vs. 20.75%, P = .921, respectively). The proportion of maternal complications was lower among patients who received HCQ, and it almost reached statistical significance (37.84% vs 58.49%, P = .054). The proportion of maternal PROM, PIH and flares in the HCQ group also was lower, but did not reach statistical significance (5.41% vs 15.09%, P = .150; 5.41% vs 11.32%, P = .332, and 32.43% vs 47.17%, P = .162, respectively).
3.5 Pregnancy outcomes according to period of pregnancy, and between the first and subsequence pregnancy
The pregnancy outcomes according to the period of pregnancy (1993–2001, 2002–2009, and 2010–2017) were determined. Overall, there was no statistically significant difference in fetal or maternal outcomes between each pregnancy period. However, when comparing the pregnancy outcomes between 2010–2017, 2002–2009, and 1993–2001, fetal outcomes among pregnancies during 2010–2017 tended to have a higher proportion of live births (80.85% vs 76.00% vs 78.95%, P = .890), full-term birth infants (36.17% vs 32.00% vs 16.67%, P = .313), but with a lower proportion of pre-term birth infants (42.55% vs 44.00% vs 63.16%, P = .294), and pregnancy loss (19.15% vs 24.00% vs 22.22%, P = .884). They also had had a higher proportion of SGA and LBW (29.79% vs 16.00% vs 5.56%, P = .070, and 48.94% vs 36.00% vs 31.58%, P = .342, respectively). The proportion of maternal complications was similar (48.94% vs 48.00% vs 55.56%, P = .868); but with a tendency for decreased proportion of PROM (8.51% vs 12.00% vs 16.67%, P = .495), PIH (8.51% vs 4.00% vs 16.67%, P = .382) and SLE flares (38.30% vs 44.00% vs 44.44%, P = .851).
The pregnancy outcomes between patients with a first pregnancy and subsequent pregnancies also were compared. Similarly, there was no significant difference in fetal and maternal outcomes between the 2 groups. However, fetal outcomes in subsequent pregnancy groups tended to have a lower proportion of live births (73.91% vs 84.44%, P = .217), full-term births (24.44% vs 37.78%, P = .172), SGA (17.78% vs 24.44%, P = .438) and LBW infants (36.96% vs 46.67%, P = .348), but higher proportion of fetal loss (26.67% vs 15.56%, P = .197). Maternal complications tended to be lower (46.67% vs 53.33%, P = .527), which was due mainly to decreased proportion of SLE flares (37.78% vs 44.44%, P = .520). The rate of caesarean section was significantly higher among subsequent pregnancies (39.39% vs 15.79%, P = .025).
3.6 Predicting factors for adverse pregnancy outcomes
In order to determine independent predicting factors for APOs, the clinical characteristics that associated with adverse fetal outcomes (pregnancy loss, prematurity, SGA and LBW), and adverse maternal outcomes (PROM, PIH and flare) were compared and are shown in Tables 2 and 3, respectively.
Table 2 Comparison of clinical characteristics of adverse fetal outcomes in pregnant SLE patients.
Successful pregnancy Pregnancy loss Pre-maturity Full term + post term SGA Non-SGA LBW Normal BW
Characteristics (n = 71) (n = 19) P value (n = 42) (n = 29) P value (n = 19) (n = 52) P value (n = 37) (n = 34) P value
Age at pregnancy (in years), mean ± SD 26.30 ± 4.55 29.31 ± 5.09 .014 26.46 ± 4.73 26.07 ± 4.34 .726 25.09 ± 3.85 26.74 ± 4.73 .178 26.12 ± 4.61 26.50 ± 4.54 .726
Disease duration prior to conception (in years), mean ± SD 4.92 ± 5.01 6.99 ± 5.37 .081 4.38 ± 3.96 5.71 ± 6.21 .574 5.20 ± 4.26 4.82 ± 5.29 .451 4.54 ± 4.08 5.34 ± 5.89 .954
Co-morbidities
Hypertension, n (%) 16 (22.54) 7 (36.84) .204 9 (21.43) 7 (24.14) .788 7 (36.84) 9 (17.31) .081 10 (27.03) 6 (17.65) .345
Diabetes, n (%) 1 (1.41) 0 >.999 1 (2.38) 0 >.999 1 (5.26) 0 .268 1 (2.70) 0 >.999
Dyslipidemia, n (%) 5 (7.04) 3 (15.79) .234 3 (7.14) 2 (6.90) >.999 4 (21.05) 1 (1.92) .016 4 (10.81) 1 (2.94) .359
APS, n (%) 2 (2.82) 1 (5.26) .513 0 2 (6.90) .163 0 2 (3.85) >.999 0 2 (5.88) .226
ANA positive, n (%) 70 (98.59) 19 (100.00) >.999 41 (97.62) 29 (100.00) >.999 19 (100.00) 51 (98.08) >.999 37 (100.00) 33 (97.06) .479
Anti-dsDNA, n (%)∗ 41/67 (61.19) 9/18 (50.00) .392 26/40 (65.00) 15/27 (55.56) .436 13/19 (68.42) 28/48 (58.33) .445 25/37 (67.57) 16/30 (53.33) .234
Anti-Sm, n (%)∗ 0/11 1/1 (100.00) .083 0/7 0/4 0/2 0/9 0/6 0/5
ACL/LAC, n (%)∗ 4/36 (11.11) 2/7 (28.57) .248 1/18 (5.56) 3/18 (16.67) .603 1/13 (7.69) 3/23 (13.04) >.999 1/19 (5.26) 3/17 (17.65) .326
Anti-Ro, n (%)∗ 16/38 (42.11) 5/8 (62.50) .293 7/17 (41.18) 9/21 (42.86) .917 6/13 (46.15) 10/25 (40.00) .715 11/23 (47.83) 5/15 (33.33) .376
Anti-La, n (%)∗ 16/38 (42.11) 4/9 (44.44) .898 7/17 (41.18) 9/21 (42.86) .917 6/13 (46.15) 10/25 (40.00) .715 11/23 (47.83) 5/15 (33.33) .376
Pregnancy loss (ever), n (%) 23 (32.39) 9 (47.37) .226 12 (28.57) 11 (37.93) .407 6 (31.58) 17 (32.69) .929 11 (29.73) 12 (35.29) .617
Cumulative number of ACR criteria, mean ± SD 5.46 ± 1.11 5.58 ± 1.35 .704 5.38 ± 1.17 5.59 ± 1.02 .446 5.42 ± 1.02 5.48 ± 1.15 .842 5.35 ± 1.06 5.59 ± 1.16 .371
Disease activity (mSLEDAI-2K) at −6M, mean ± SD 1.34 ± 2.43 3.16 ± 5.05 .325 1.36 ± 2.44 1.31 ± 2.46 .960 1.42 ± 2.48 1.31 ± 2.44 .874 1.38 ± 2.53 1.29 ± 2.36 .933
Disease activity (mSLEDAI-2K) at conception, mean ± SD 1.58 ± 2.74 3.16 ± 5.22 .562 1.81 ± 2.98 1.24 ± 2.36 .385 2.16 ± 2.99 1.36 ± 2.64 .222 1.92 ± 3.22 1.20 ± 2.08 .566
Remission, n (%) 45 (63.38) 12 (63.16) .321 25 (59.52) 20 (68.97) .629 10 (52.63) 35 (67.31) .444 23 (62.16) 22 (64.71) .955
Mild, n (%) 19 (26.76) 3 (15.79) 13 (30.95) 6 (20.69) 6 (31.58) 13 (25.00) 10 (27.03) 9 (26.47)
Moderate and high, n (%) 7 (9.86) 4 (21.05) 4 (9.52) 3 (10.34) 3 (15.79) 4 (7.69) 4 (10.81) 3 (8.82)
SDI score at conception, mean ± SD 0.35 ± 0.66 0.58 ± 0.90 .400 0.36 ± 0.62 0.34 ± 0.72 .612 0.21 ± 0.42 0.40 ± 0.72 .463 0.24 ± 0.55 0.47 ± 0.75 .169
Active organ involvement during pregnancy
Renal 30 (42.25) 10 (52.63) .419 23 (54.76) 7 (24.14) .010 13 (68.42) 17 (32.69) .007 24 (64.86) 6 (17.65) <.001
Mucocutaneous 23 (32.39) 4 (21.05) .338 12 (28.57) 11 (37.93) .407 4 (21.05) 19 (36.54) .217 9 (24.32) 14 (41.18) .130
Vasculitis 2 (2.82) 1 (5.26) .513 1 (2.38) 1 (3.45) >.999 1 (5.26) 1 (1.92) .466 1 (2.70) 1 (2.94) >.999
Arthritis 2 (2.82) 0 >.999 2 (4.76) 0 .510 0 2 (3.85) >.999 1 (2.70) 1 (2.94) >.999
Hematologic 8 (11.27) 0 .125 6 (14.29) 2 (6.90) .333 4 (21.05) 4 (7.69) .197 5 (13.51) 3 (8.82) .532
Medication at conception
Prednisolone, n (%) 56 (78.87) 17 (89.47) .294 32 (76.19) 24 (82.76) .505 15 (78.95) 41 (78.85) .993 31 (83.78) 25 (73.53) .290
Dose (in mg/day), mean ± SD 9.11 ± 9.38 16.25 ± 16.58 .058 9.53 ± 9.56 8.54 ± 9.32 .412 12.50 ± 12.32 7.86 ± 7.88 .162 9.11 ± 9.39 9.10 ± 9.57 .823
Prednisolone >10 mg/day 10 (14.08) 6 (31.58) .076 6 (14.29) 4 (13.79) .953 5 (26.32) 5 (9.62) .073 6 (16.22) 4 (11.76) .590
Hydroxychloroquine, n (%) 29 (40.85) 8 (42.11) .921 15 (35.71) 14 (48.28) .290 6 (31.58) 23 (44.23) .337 13 (35.14) 16 (47.06) .307
Dose (in mg/day), mean ± SD 191.38 ± 86.67 256.25 ± 129.39 .144 183.33 ± 79.43 200.00 ± 96.08 .762 166.67 ± 51.64 197.83 ± 93.52 .533 165.38 ± 55.47 212.50 ± 102.47 .275
Immunosuppressive drug† 18 (25.35) 4 (21.05) .699 10 (23.81) 8 (27.59) .719 5 (26.32) 13 (25.00) .910 12 (32.43) 6 (17.65) .153
Mycophenolate mofetil, n (%) 4 (5.63) 0 .575 2 (4.76) 2 (6.90) >.999 1 (5.26) 3 (5.77) >.999 3 (8.11) 1 (2.94) .615
Cyclophosphamide, n (%) 3 (4.23) 3 (15.79) .106 3 (7.14) 0 .265 1 (5.26) 2 (3.85) >.999 3 (8.11) 0 .241
Azathioprine, n (%) 10 (14.08) 0 .083 5 (11.90) 5 (17.24) .525 3 (15.79) 7 (13.46) .803 6 (16.22) 4 (11.76) .590
Cyclosporine, n (%) 2 (2.82) 1 (5.26) .513 0 2 (6.90) .163 0 2 (3.85) >.999 1 (2.70) 1 (2.94) >.999
Flare during pregnancy 32 (45.07) 5 (26.32) .140 23 (54.76) 9 (31.03) .048 11 (57.89) 21 (40.38) .189 22 (59.46) 10 (29.41) .011
Table 3 Comparison of clinical characteristics of adverse maternal outcomes in pregnant SLE patients.
Premature rupture of membrane Pregnancy induced hypertension Flares
Characteristics Yes (n = 10) No (n = 80) P value Yes (n = 8) No (n = 82) P value Yes (n = 37) No (n = 53) P value
Age at pregnancy (in years), mean ± SD 28.85 ± 4.38 26.70 ± 4.82 .182 25.92 ± 3.65 27.03 ± 4.90 .535 26.89 ± 4.75 26.97 ± 4.88 .937
Disease duration prior to conception (in years), mean ± SD 3.81 ± 3.06 5.55 ± 5.31 .521 4.67 ± 6.25 5.43 ± 5.04 .257 5.67 ± 5.45 5.14 ± 4.92 .608
Co-morbidities
Hypertension, n (%) 1 (10.00) 22 (27.50) .232 1 (12.50) 22 (26.83) .375 14 (37.84) 9 (16.98) .026
Diabetes, n (%) 0 1 (1.25) >.999 0 1 (1.22) >.999 0 1 (1.89) >.999
Dyslipidemia, n (%) 0 8 (10.00) .295 0 8 (9.76) .355 3 (8.11) 5 (9.43) .828
APS, n (%) 0 3 (3.75) >.999 0 3 (3.66) >.999 2 (5.41) 1 (1.89) .566
ANA positive, n (%) 10 (100.00) 79 (98.75) >.999 7 (87.50) 82 (100.00) .089 37 (100.00) 52 (98.11) >.999
Anti-dsDNA, n (%)∗ 5/9 (55.56) 45/76 (59.21) .833 5/7 (71.43) 45/78 (57.69) .479 20/35 (57.14) 30/50 (60.00) .792
Anti-Sm, n (%)∗ 0/1 1/11 (9.09) >.999 0/1 1/11 (9.09) >.999 0/4 1/8 (12.50) >.999
ACL/LAC, n (%)∗ 0/4 6/39 (15.38) >.999 0/3 6/40 (15.00) >.999 2/16 (12.50) 4/27 (14.81) >.999
Anti-Ro, n (%)∗ 1/4 (25.00) 20/42 (47.62) .614 2/4 (50.00) 19/42 (45.24) >.999 6/15 (40.00) 15/31 (48.39) .592
Anti-La, n (%)∗ 1/4 (25.00) 19/43 (44.19) .626 2/4 (50.00) 18/43 (41.86) >.999 6/15 (40.00) 14/32 (43.75) .808
Pregnancy loss (ever), n (%) 3 (30.00) 29 (36.25) .697 2 (25.00) 30 (36.59) .513 9 (24.32) 23 (43.40) .063
Cumulative number of ACR criteria, mean ± SD 5.30 ± 1.06 5.51 ± 1.17 0.586 5.62 ± 0.52 5.48 ± 1.20 .518 5.54 ± 1.14 5.45 ± 1.17 .725
Disease activity (mSLEDAI-2K) at -6M, mean ± SD 0.40 ± 1.26 1.89 ± 3.35 .116 0.25 ± 0.71 1.86 ± 3.33 .163 1.70 ± 3.44 1.74 ± 3.09 .696
Disease activity (mSLEDAI-2K) at conception, mean ± SD 0.70 ± 1.34 2.06 ± 3.59 .400 1.00 ± 2.14 2.00 ± 3.54 .454 2.16 ± 3.92 1.74 ± 3.09 .624
Remission, n (%) 7 (70.00) 50 (62.50) 0.450 6 (75.00) 51 (62.20) .704 22 (59.46) 35 (66.04) 0.816
Mild, n (%) 3 (30.00) 19 (23.75) 1 (12.50) 21 (25.61) 10 (27.03) 12 (22.64)
Moderate and high, n (%) 0 11 (13.75) 1 (12.50) 10 (12.20) 5 (13.51) 6 (11.32)
SDI score at conception, mean ± SD 0.50 ± 0.85 0.39 ± 0.70 .728 0 ± 0 0.44 ± 0.74 .079 0.54 ± 0.80 0.30 ± 0.64 .120
Active organ involvement during pregnancy
Renal 6 (60.00) 34 (42.50) .294 5 (62.50) 35 (42.68) .282 27 (72.97) 13 (24.53) <.001
Mucocutaneous 4 (40.00) 23 (28.75) .464 4 (50.00) 23 (28.05) .234 17 (45.95) 10 (18.87) .006
Vasculitis 0 3 (3.75) >.999 0 3 (3.66) >.999 3 (8.11) 0 .066
Arthritis 0 2 (2.50) >.999 0 2 (2.44) >.999 1 (2.70) 1 (1.89) >.999
Hematologic 2 (20.00) 6 (7.50) .190 3 (37.50) 5 (6.10) .003 8 (21.62) 0 <.001
Medication at conception
Prednisolone, n (%) 8 (80.00) 65 (81.25) .924 4 (50.00) 69 (84.15) .039 29 (78.38) 44 (83.02) .580
Dose (in mg/day), mean ± SD 5.94 ± 2.65 11.36 ± 12.78 .423 19.38 ± 27.26 10.27 ± 10.41 .755 8.88 ± 7.89 12.02 ± 13.63 .958
Prednisolone >10 mg/day 0 16 (20.00) .119 1 (12.50) 15 (18.29) .683 5 (13.51) 11 (20.75) .377
Hydroxychloroquine, n (%) 2 (20.00) 35 (43.75) .150 2 (25.00) 35 (42.68) .332 12 (32.43) 25 (47.17) .162
Dose (in mg/day), mean ± SD 125.00 ± 106.07 210.00 ± 98.37 .223 150.00 ± 70.71 208.57 ± 100.36 .382 208.33 ± 129.39 204.00 ± 84.06 .797
Immunosuppressive drug† 2 (20.00) 20 (25.00) .729 0 22 (26.83) .092 7 (18.92) 15 (28.30) .308
Mycophenolate mofetil, n (%) 1 (10.00) 3 (3.75) .381 0 4 (4.88) >.999 2 (5.41) 2 (3.77) >.999
Cyclophosphamide, n (%) 0 6 (7.50) .370 0 6 (7.32) .428 1 (2.70) 5 (9.43) .208
Azathioprine, n (%) 1 (10.00) 9 (11.25) .906 0 10 (12.20) .295 4 (10.81) 6 (11.32) .940
Cyclosporine, n (%) 0 3 (3.75) >.999 0 3 (3.66) >.999 0 3 (5.66) .266
Flare during pregnancy 8 (80.00) 29 (36.25) .008 5 (62.50) 32 (39.02) .198
Factors that might be associated with adverse fetal and maternal outcomes, and those that had a statistical difference with a P value of <.2 in the univariate analysis (Tables 2 and 3) were included in the multiple logistic regression analysis (Tables 4 and 5). Independent predicting factors that increased the risk of fetal loss included age at pregnancy of ≥25 years (AOR [95% CI]) 4.15 [1.10–15.72], P = .036), and ever having renal involvement (9.21 [1.03–82.51], P = .047). Prednisolone used (>10 mg/day) at conception almost reached a predicting factor for fetal loss (3.89 [0.99–15.20], P = .051). Renal involvement during pregnancy independently predicted prematurity (6.02 [1.77–20.52], P = .004), and SGA (4.46 [1.44–13.78], P = .009) and LBW infants (10.01 [3.07–32.62], P < .001). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception independently reduced the risk of prematurity (0.11 [0.02–0.85], P = .034). SLE flares and hematologic involvement during pregnancy independently predicted PROM (8.45 [1.58–45.30], P = .013) and PIH (9.24 [1.70–50.24], P = .010), respectively. Independent predicting factors for SLE flares during pregnancy included the presence of cutaneous vasculitis (AOR [95% CI]) 33.87 [1.05–1094.65], P = .047), and renal (31.89 [6.66–152.69], P < .001), mucocutaneous (9.17 [1.83–45.90], P = .007) and hematologic involvement (128.00 [4.60–3,564.46], P = .004). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception independently reduced the risk of SLE flares during pregnancy (0.08 [0.01–0.68, P = .021).
Table 4 Univariable analysis and multiple logistic regression analysis of factors associated with adverse fetal outcomes in pregnant SLE patients.
Pregnancy loss Prematurity Small for gestational age Low birth weight
Characteristics N1 n OR (95% CI) P value N2 n OR (95% CI) P value n OR (95% CI) P value n OR (95% CI) P value
Age at pregnancy
<25 years 39 4 3.64 35 21 0.93 13 0.34 19 0.84
≥25 years 51 15 (1.01–16.37) .027a 36 21 (0.32–2.67) .886 6 (0.09–1.16) .051 18 (0.30–2.37) .718
Disease duration prior to conception
<5 years 56 8 2.87 48 28 1.11 13 0.95 26 0.78
≥5 years 34 11 (0.90–9.34) .042 23 14 (0.36–3.52) .839 6 (0.25–3.28) .929 11 (0.25–2.36) .617
Hypertension
No 67 12 2.00 55 33 0.86 12 2.79 27 1.73
Yes 23 7 (0.56–6.64) .204 16 9 (0.24–3.15) .788 7 (0.71–10.44) .081 10 (0.48–6.59) .345
Previous pregnancy
0 45 7 1.97 38 21 1.42 11 0.78 21 0.76
≥1 45 12 (0.62–6.61) .196 33 21 (0.49–4.12) .474 8 (0.23–2.56) .655 16 (0.27–2.15) .568
Pregnancy loss (ever)
No 58 10 1.88 48 30 0.65 13 0.95 26 0.78
Yes 32 9 (0.58–5.92) .226 23 12 (0.21–2.03) .408 6 (0.25–3.28) .929 11 (0.25–2.36) .617
Renal disorder (ever)
No 18 1 5.67 17 6 3.67 3 1.96 5 3.49
Yes 72 18 (0.76–249.73) .071b 54 36 (1.02–13.92) .022 16 (0.45–12.00) .330 32 (0.96–14.27) .032
SLE disease activity at conception
Remission and mild 79 15 2.44 64 38 0.91 16 2.25 33 1.25
Moderate and high 11 4 (0.46–11.06) .186 7 4 (0.14–6.76) .909 3 (0.29–14.72) .311 4 (0.19–9.22) .779
Prednisolone >10 mg/day at conception
No 74 13 2.82 61 36 1.04 14 3.36 31 1.45
Yes 16 6 (0.70–10.38) .076c 10 6 (0.22–5.55) .953 5 (0.66–16.66) .073 6 (0.31–7.68) .590
IM drugs used at conception
No 68 15 0.78 53 32 0.82 14 1.07 25 2.24
Yes 22 4 (0.17–2.93) .699 18 10 (0.24–2.83) .719 5 (0.25–3.99) .910 12 (0.65–8.33) .152
Prednisolone >10 mg/day and IM drugs used at conception
No 82 17 1.27 65 40 0.31 17 1.41 34 0.91
Yes 8 2 (0.12–7.98) .778 6 2 (0.03–2.40) .179d 2 (0.12–10.86) .704 3 (0.11–7.33) .914
HCQ used during pregnancy
No 47 11 0.75 36 23 0.67 11 0.67 21 0.60
Yes 43 8 (0.23–2.33) .577 35 19 (0.23–1.93) .410 8 (0.20–2.20) .464 16 (0.21–1.70) .287
Organ involvement during Pregnancy
Cutaneous vasculitis
No 87 18 1.92 69 41 0.68 18 2.83 36 0.92
Yes 3 1 (0.03–38.45) .598 2 1 (0.01–55.50) .789 1 (0.03–226.66) .451 1 (0.01–74.11) .952
Arthritis
No 88 19 0.71 69 40 3.64 19 0.52 36 0.92
Yes 2 0 (0.03–15.47) .829 2 2 (0.17–78.70) .410 0 (0.02–11.28) .676 1 (0.01–74.11) .952
Renal
No 50 9 1.52 41 19 3.80 6 4.46 13 8.62
Yes 40 10 (0.48–4.78) .419 30 23 (1.21–12.72) .010e 13 (1.28–16.62) .007f 24 (2.54–31.31) <.001g
Mucocutaneous
No 63 15 0.56 48 30 0.65 15 0.46 28 0.46
Yes 27 4 (0.12–2.03) .338 23 12 (0.21–2.03) .408 4 (0.10–1.76) .217 9 (0.14–1.42) .130
Hematologic
No 82 19 0.19 63 36 2.25 15 3.20 32 1.61
Yes 8 0 (0.01–3.47) .264 8 6 (0.36–24.23) .333 4 (0.52–19.11) .115 5 (0.28–11.21) .532
Flares during pregnancy
No 53 14 0.44 39 19 2.69 8 2.03 15 3.52
Yes 37 5 (0.11–1.47) .140 32 23 (0.90–8.28) .048 11 (0.62–6.84) .189 22 (1.18–10.70) .011
Table 5 Univariable analysis and multiple logistic regression analysis of factors associated with adverse maternal outcomes in pregnant SLE patients.
Premature rupture of the membrane Pregnancy induced hypertension Flares
Characteristics N n OR 95% CI P value n OR 95% CI P value n OR 95% CI P value
Age at pregnancy
<25 years 39 2 Ref. 4 Ref. 18 Ref.
≥25 years 51 8 3.44 0.62–34.83 .114 4 0.74 0.13–4.31 .690 19 0.69 (0.27–1.76) .395
Disease duration prior to conception
<5 years 56 7 Ref. 6 Ref. 22 Ref.
≥5 years 34 3 0.68 0.10–3.25 .590 2 0.52 0.05–3.17 .435 15 1.22 (0.47–3.15) .652
Hypertension
No 67 9 Ref. 7 Ref. 23 Ref.
Yes 23 1 0.29 0.01–2.36 .232 1 0.39 0.01–3.35 .375 14 2.98 (1.01–8.99) .026
Previous pregnancy
0 45 4 Ref. 4 Ref. 20 Ref.
≥1 45 6 1.58 0.34–8.16 .502 4 1.00 0.17–5.76 >.999 17 0.76 (0.30–1.91) .520
Pregnancy loss (ever)
No 58 7 Ref. 6 Ref. 28 Ref.
Yes 32 3 0.75 0.12–3.63 .697 2 0.58 0.05–3.52 .514 9 0.42 (0.14–1.15) .063
Renal disorder (ever)
No 18 1 Ref. 0 Ref. 5 Ref.
Yes 72 9 2.43 0.30–112.60 .402 8 4.88 0.27–88.50 .284 32 2.08 (0.61–8.19) .199
SLE disease activity at conception
Remission and mild 79 10 Ref. 7 Ref. 32 Ref.
Moderate and high 11 0 0.29 0.02–5.26 .401 1 1.03 0.02–9.54 .980 5 1.22 (0.27–5.27) .755
Prednisolone >10 mg/day at conception
No 74 10 Ref. 7 Ref. 32 Ref.
Yes 16 0 0.19 0.01–3.34 .254 1 0.64 0.01–5.64 .682 5 0.60 (0.15–2.11) .377
IM drugs used at conception
No 68 8 Ref. 8 Ref. 30 Ref.
Yes 22 2 0.75 0.07–4.22 .729 0 0.16 0.01–2.85 .212 7 0.59 (0.18–1.79) .308
Prednisolone >10 mg/day and IM drugs used at conception
No 82 10 Ref. 8 Ref. 36 Ref.
Yes 8 0 0.41 0.02–7.57 .546 0 0.52 0.03–9.74 .659 1 0.18 (0.00–1.55) .085c
HCQ used during pregnancy
No 47 8 Ref. 5 Ref. 20 Ref.
Yes 43 2 0.24 0.02–1.31 .062 3 0.63 0.09–3.50 .542 17 0.88 (0.35–2.22) .771
Organ involvement during pregnancy
Cutaneous vasculitis
No 87 10 Ref. 8 Ref. 34 Ref.
Yes 3 0 1.05 0.05–21.88 .973 0 1.34 0.06–28.11 .852 3 10.86 (0.54–216.71) .119d
Arthritis
No 88 10 Ref. 8 Ref. 36 Ref.
Yes 2 0 1.50 0.07–33.32 .799 0 1.89 0.08–42.79 .688 1 1.44 (0.02–115.53) .796
Renal
No 50 4 Ref. 3 Ref. 10 Ref.
Yes 40 6 2.03 0.44–10.49 .294 5 2.24 0.40–15.24 .282 27 8.31 (2.90–24.34) <.001e
Mucocutaneous
No 63 6 Ref. 4 Ref. 20 Ref.
Yes 27 4 1.65 0.31–7.69 .464 4 2.56 0.43–14.84 .196 17 3.66 (1.29–10.54) .006f
Hematologic
No 82 8 Ref. 5 Ref. 29 Ref.
Yes 8 2 3.08 0.26–21.22 .190 3 9.24 1.07–64.46 .003b 8 30.83 (1.72–553.28) .020g
Flares during pregnancy
No 53 2 Ref. 3 Ref.
Yes 37 8 7.03 1.26–70.80 .008a 5 2.60 0.46–17.73 .198
4 Discussion
Despite significant improvement in medical care for pregnant SLE patients, their APOs are still a significant issue.[5,18] Fetal loss (both spontaneous abortion and intra-uterine death), pre-term birth, intra-uterine growth retardation, SGA and LBW in the fetus, and PIH, pre-eclampsia/eclampsia and flares in the mother are among the major APOs of concern. Reports on SLE patients with APOs varied greatly among studies. This could be explain partly by the difference in time period of the study and ethnicity and socioeconomic status of the patients, as well as SLE disease activity prior to and at the time of conception, organ involvement at conception, rate and organ of flares, and prevalence of ACL/LAC or anti-phospholipid syndrome in the population studied.[1,3,19]
Progressive improvement in pregnancy outcomes over a 25-year period was observed in this study. The proportion of successful pregnancies tended to improve with an increased proportion of full-term births and decreased proportion of pre-term infants. An increased proportion of infants with SGA and LBW had slightly decreased mean fetal birth weight; although all of these changes did not reach statistical significance. The improvement in pregnancy outcomes in Thai SLE patients was similar overtime to that in many previous reports.[5,18,20,21] However, the reason for the increased frequency of SGA and LBW was not clear, despite more frequent full-term birth infants.
This study also found that pregnancy outcomes of subsequent pregnancies in SLE patients showed a slightly decreased proportion of live births, full-term births, and SGA and LBW infants, but with slightly increased proportion of fetal loss, particularly among medical terminations. The lower proportion of SGA and LBW in the subsequent pregnancies in this study was similar to that of Wallanius et al,[22] but different from that of Korese et al,[23] who found that the fetal and maternal outcomes were almost similar between the first and subsequent pregnancies, except for the latter having slightly lower pre-term births. Reasons for the higher proportion of medical terminations in subsequent pregnancies in this study were not clear, but this might have been due to decisions made by the mothers and physicians, who were afraid of severe maternal or fetal complications if the pregnancy continued, and the patients probably had a baby already from the previous pregnancy. The proportion of cesarean section delivery among the subsequent pregnancies in this study was significantly (approximately 2 times) higher than that in the first pregnancy, which was similar to that reported by Wallenius et al.[22] This could be explained by the perception of the patients and physicians in that they were afraid of possible uterine rupture during delivery.
The PIH and eclampsia prevalence of 8.89% and 1.11%, respectively, in this study was in line with many previous reports that showed prevalence of 0–19% and 0–20% for PIH[20,23–27] and pre-eclampsia, respectively[20,23–27]. However, when looking at details, studies with a high incidence of PIH had a rather low incidence of pre-eclampsia or vise-versa; except for that reported by Wu et al,[27] and Kroese et al.[23] The reason for the discordance among these reports was unclear. It is not easy in clinical practice to differentiate between PIH and pre-eclampsia in pregnant patients with pre-existing hypertension and renal disease, as hypertension is an important clinical feature in both conditions. For example, a patient with pre-existing hypertension and some degree of proteinuria has slightly increasing proteinuria (without blood cells or cellular casts in the urine, with decreasing complement level, or increasing anti-dsDNA), and elevated blood pressure in the late course of pregnancy. In this situation, many physicians might consider PIH, while others consider pre-eclampsia. A definite diagnosis of these 2 conditions probably can be made only upon patient follow-up of the patients whether both hypertension and proteinuria are resolved or returned to baseline level prior to the development of hypertension and increasing proteinuria during the post-partum period. There were no pre-eclampsia cases in this study. As patients with increasing hypertension and slightly increasing proteinuria without active urine sediment had their blood pressure, but not the proteinuria, returned to normal or baseline during the post-partum period. These patients were considered to have PIH and not pre-eclampsia.
Similar to the differentiation between PIH and pre-eclampsia, differentiation between pre-eclampsia and active nephritis flare is another challenging issue in clinical practice. Several reviews suggest that the presence of extra-renal manifestation, past history of lupus nephritis, presence of or increasing proteinuria at the early trimester of pregnancy, presence of new hypertension onset, presence of active urinary sediments, decreasing serum complement levels, increasing anti-dsDNA levels and normal serum uric acid, favor active nephritis. However, if the aforementioned conditions occur late in the pregnancy, and the patient does not have decreasing complement or increasing anti-dsDNA levels, differential diagnosis between active nephritis and pre-eclampsia would be more difficult.[28–30] The situation would be more complicated if the patient has underlying hypertension prior to pregnancy or slight proteinuria prior to conception. Furthermore, these 2 conditions can co-exist in the same patients.[31] Some authors have suggested performing a kidney biopsy in the latter condition,[29,32] as the management of active lupus nephritis and pre-eclampsia is different. Again, sometimes the diagnosis can be made only upon delivery of the fetus when the above conditions disappear or return to normal.[3] All of the patients who had significantly increasing proteinuria in this study also had active urine sediment, and the degree of proteinuria did not return to normal or baseline at the end of the post-partum period. All of them also showed renal response to an increasing dose of corticosteroid and immunosuppressive drugs, therefore, they were more likely to have active nephritis flare rather than pre-eclampsia.
The pathogenic mechanisms of PIH and pre-eclampsia are not clear, but have been reviewed widely, and included innate immunity,[33] bioactive factors (such as inflammatory cytokines, angiogenetic factors, growth factors, etc.),[34,35] oxidative stress,[36] placental vascular maladaptation,[37] and endothelial dysfunction.[38,39] Among these, endothelial dysfunction is the most likely underlying mechanism,[39] which causes imbalance between an endothelial-derived vasodilator (such as nitric oxide and prostacyclin) and vasoconstrictors (such as endothelin-1, thromboxane A2), leading to the promotion of vasoconstriction, hypertension, and pre-eclampsia. Placenta ischemia stimulates the release of several bioactive factors and inflammatory cytokines that target the endothelial cells that lead to generalized endothelial cell dysfunction, which in turn causes vascular remodeling, increased arterial stiffness, and hypertension. Current treatment options of pre-eclampsia are limited. Only low dose aspirin has been shown as effective and is recommended by several international obstetrics and gynecologists guidelines for use in preventing pre-eclampsia in high risk patients.[40] Unfortunately, the effect of low dose aspirin on pregnancy outcomes was not determined in this study.
The effect of HCQ use on pregnancy outcomes also has been of interest in lupus pregnancy, although many previous studies could not find a significant difference in overall SLE pregnancy outcomes between HCQ users and non-users.[41–43] However, some studies showed some beneficial effects of HCQ use during pregnancy, including lower rate of fetal loss and pre-term births,[20,44] intra-uterine growth restriction (IUGR) in the fetus,[44] longer duration of pregnancy,[42] flare prevention,[43,45] and decreased PIH.[46] Although no significant difference in APOs among HCQ users and non-users was demonstrated in this study, there tended to be fewer maternal complications among HCQ users, particularly in a lower proportion of PROM, PIH and SLE flares.
Several factors have been identified in association with APOs in pregnant patients with SLE. These have included the presence of renal involvement or active nephritis,[20,24,47–53] SLE flares during pregnancy,[7,24,50,53,54] active disease prior to or during pregnancy,[20,50,54–56] hypertension,[7,24,25,54–57] presence of anti-phospholipid antibodies (APL) and/or lupus anti-coagulants,[7,20,23,24,50,53,54,56,57] cytopenia,[41,50,52,54] and hypocomplementemia.[20,25,50,54,56,58,59] This study also confirmed that renal involvement during pregnancy was associated with poor pregnancy outcomes, in both the fetus and mother. However, the presence of hypertension only associated with maternal flares.
Although APOs have been reported in several studies, only a few identified independent predicting factors for adverse fetal and maternal outcomes. In addition, the results of these predicting factors also were inconsistent. For example, Cortes-Hernandez et al[25] found that the presence of ACL and hypertension during pregnancy were independent predicting factors for poor fetal outcomes, whereas the presence of anti-β2-glycoprotein-1, hypertension at conception and hypocomplemetemia were independent predicting factors for fetal loss. Kwok et al[24] found that hypertension was an independent predicting factor for fetal loss, nephritis for SGA, low serum albumin for IUGR and SLE flares for prematurity among infants; and nephritis was an independent predicting factor for SLE flares, and hypertension and high disease activity for pre-eclampsia among mothers. Ko et al[26] found that the presence of APL antibodies was an independent predicting factor for fetal loss and pre-term births, and active disease for pre-term births. Active SLE and SLE flares were independent predicting factors for PIH and IUGR among mothers. Buyon et al[41] found that the presence of LAC, hypertension, high disease activity, maternal flares, and thrombocytopenia were predictors of APOs. Lui et al[60] found that pre-eclampsia/eclampsia and thrombocytopenia were independent predicting factors for fetal loss and SLE flares in mothers. Pre-eclampsia/eclampsia also was an independent predicting factor for pre-term birth among infants. Borella et al[56] found that hypertension was an independent predicting factor for fetal loss, miscarriage and SGA, and anti-phospholipid syndrome (APS) for prematurity in infants; whereas LAC was an independent predicting factor for pre-eclampsia, and active disease at −6 M for PROM. Kalok et al[6] found that SLE flares and active disease were predicting factors for fetal loss and pre-term birth, and also SLE flares for SGA among infants. Active SLE was an independent predicting factor for SLE flares and lupus nephritis, while SLE flares and the presence of APL antibodies were independent predicting factors for pre-eclampsia among mothers. Wu et al[59] recently found that unplanned pregnancy, hypocomplementemia and urine protein >1.0 gm/day were independent predicting factors for fetal loss. This study found that age >25 years and ever having renal involvement were independent predicting factors for fetal loss, renal involvement during pregnancy, prematurity, SGA and LBW among infants. SLE flare during pregnancy and hematologic involvement were independent predicting factors for PROM and PIH, respectively, among mothers. It was interesting that the use of prednisolone (>10 mg/day) and immunosuppressive drugs at conception was an independent protecting factor for prematurity. The presence of cutaneous vasculitis, and renal, mucocutaneous and hematologic involvement during pregnancy was an independent predicting factor for SLE flares; while the use of prednisolone (>10 mg/day) and immunosuppressive drugs at the time of conception reduced the risk of SLE flares independently. The predicting factors identified from this study were similar to many of those mentioned in the aforementioned studies. However, this study could not demonstrate that the presence of ACL/LAC was an independent factor for poor pregnancy outcomes. This might relate to the small number of patients with poor pregnancy outcome, who were among those with a positive test for these antibodies, as previously discussed. A larger study, including more patients with APL/LAC, needs to be carried out in order to verify this association in Thai patients.
The use of mSLEDAI-2K, the modified SFI and modified SLE disease activity severity score would have caused a limitation in this study. The SLE disease activity or flares would be underestimated (as the score for anti-dsDNA and complement would not be counted), making it difficult to compare this study with those that used scores from the original version. However, the mSLEDAI-2K has been shown to correlate very well (r = 0.924) with the original SLEDAI-2K.[13] In addition, use of the mSLEDAI-2K score in this study reflects real world practice, as many institutions could not perform anti-dsDNA and complements routinely. The small number of patients with positive ACL/LAC did not demonstrate the effect of these antibodies on APOs clearly. However, all of the patients in this study were taken care of by the same group of rheumatologists, who collectively made more uniformed therapeutic decisions, which should add more strength to the outcomes.
5 Conclusion
This study showed that pregnancy outcomes in Thai patients with SLE has improved over a 25-year period. However, a significant number of APOs were still observed. Renal involvement and flares during pregnancy were associated with both poor fetal and maternal outcomes. The beneficial effect of HCQ in lupus pregnancy was not demonstrated clearly, but there was a trend in favor of better pregnancy outcomes among the HCQ users. Age ≥ 25 years at conception, the presence of or ever having renal involvement during pregnancy, presence of SLE flare and hematologic involvement during pregnancy were predicting factors for poor pregnancy outcomes. Cutaneous vasculitis, and renal, hematologic and mucocutaneous involvement during pregnancy predicted SLE flare. The effect of APL/LAC on pregnancy outcomes in Thai populations needs further investigations.
Acknowledgments
The authors thank Mrs. Waraporn Sukitawut, Ms. Saowanee Pantana and Ms. Phimwalan Konkaeo for their secretarial assistance.
Author contributions
Conceptualization: Worawit Louthrenoo, Thananant Trongkamolthum, Nuntana Kasitanon, Antika Wongthanee.
Data curation: Worawit Louthrenoo, Thananant Trongkamolthum.
Formal analysis: Worawit Louthrenoo, Antika Wongthanee.
Investigation: Worawit Louthrenoo, Thananant Trongkamolthum.
Methodology: Worawit Louthrenoo, Thananant Trongkamolthum.
Supervision: Worawit Louthrenoo.
Validation: Worawit Louthrenoo, Antika Wongthanee.
Visualization: Worawit Louthrenoo, Antika Wongthanee.
Writing – original draft: Worawit Louthrenoo, Thananant Trongkamolthum.
Writing – review & editing: Worawit Louthrenoo, Thananant Trongkamolthum, Nuntana Kasitanon, Antika Wongthanee.
Abbreviations: 95% CI = 95% confidence intervals, ACL = anti-cardiolipin antibodies, ACR = American College of Rheumatology, ANA = antinuclear antibodies, Anti-dsDNA = anti-double stranded DNA antibodies, Anti-Ro = anti-Ro antibodies, Anti-Sm = anti-Smith antibodies, AOR = adjusted odds ratio, APL = anti-phospholipid antibodies, APO = adverse pregnancy outcomes, APS = anti-phospholipid syndrome, HCQ = hydroxychloroquine, HELLP syndrome = hemolysis, elevated liver enzymes, and low platelet count syndrome, IM drugs = immunosuppressive drugs, LAC = lupus coagulants, LBW = low birth weight, mSLEDAI-2K = modified Systemic Lupus Erythematosus Disease Activity Index-2000, OR = odds ratio, PGA = physician global assessment, PIH = pregnancy induced hypertension, PPH = post-partum hemorrhage, PROM = premature rupture of membrane, SDI = the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, SFI = the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE flare index, SGA = small for gestational age, SLE = systemic lupus erythematosus, VLBW = very low birth weight.
How to cite this article: Louthrenoo W, Trongkamolthum T, Kasitanon N, Wongthanee A. Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus: a STROBE-compliant study. Medicine. 2021;100:5(e24553).
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
∗ twin pregnancy.
† maternal complications (PROM + oligohydramnios = 1, PROM + post-partum hemorrhage = 1, PROM + PIH = 1, PIH + eclampsia = 1), ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, LBW = low birth weight, PIH = pregnancy induced hypertension, PPH = post-partum hemorrhage, PROM = premature rupture of membrane, SGA = small for gestational age.
∗ number of positive tests/number tested.
† excluding hydroxychloroquine, −6 M = 6 months prior to conception, ACR = American College of Rheumatology, ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, APS = anti-phospholipid syndrome, BW = birth weight, LBW = low birth weight, SDI = Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index, mSLEDAI-2K = modified systemic lupus erythematosus disease activity index – 2000, SGA = small for gestational age.
∗ number of positive tests/number tested.
† excluding hydroxychloroquine, −6 M = 6 months prior to conception, ACR = American College of Rheumatology, ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, APS = anti-phospholipid syndrome, SDI = Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index, SLEDAI-2K = systemic lupus erythematosus disease activity index – 2000.
a AOR (95% CI) = 4.15 (1.10–15.72), P = .036.
b AOR (95% CI) = 9.21 (1.03–82.51), P = .047.
c AOR (95% CI) = 3.89 (0.99–15.20), P = .051.
d AOR (95% CI) = 0.11 (0.02–0.85), P = .034.
e AOR (95% CI) = 6.0 (1.77–20.52), P = .004.
f AOR (95% CI) = 4.46 (1.44–13.78), P = .009.
g AOR (95% CI) = 10.01 (3.07–32.62), P < .001.
HCQ = hydroxychloroquine, IM drugs = immunosuppressive drugs, excluding HCQ, n = number of pregnancies with positive conditions, N1 = number of pregnancies, N2 = number of pregnancies with live births.
a AOR (95% CI) = 8.45 (1.58–45.30), P = .013.
b AOR (95% CI) = 9.24 (1.70–50.24), P = .010.
c AOR (95% CI) = 0.08 (0.01–0.68), P = .021.
d AOR (95% CI) = 33.87 (1.05–1,094.65), P = .047.
e AOR (95% CI) = 31.89 (6.66–152.69), P < .001.
f AOR (95% CI) = 9.17 (1.83–45.90), P = .007.
g AOR (95% CI) = 128.00 (4.60–3564.46), P = .004.
HCQ = hydroxychloroquine, IM drugs = immunosuppressive drugs, excluded HCQ, n = number of pregnancies with positive conditions, N1 = number of pregnancies, N2 = number of pregnancies with live birth. | MYCOPHENOLATE MOFETIL | DrugsGivenReaction | CC BY-NC | 33592909 | 19,221,827 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Low birth weight baby'. | Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus: A STROBE-compliant study.
Studies on predicting factors for adverse pregnancy outcomes (APOs) in Thai patients with systemic lupus erythematosus (SLE) are limited. This retrospective observation study determined APOs and their predictors in Thai patients with SLE.Medical records of pregnant SLE patients in a lupus cohort, seen from January 1993 to June 2017, were reviewed.Ninety pregnancies (1 twin pregnancy) from 77 patients were identified. The mean age at conception was 26.94 ± 4.80 years. At conception, 33 patients (36.67%) had active disease, 23 (25.56%) hypertension, 20 (22.22%) renal involvement, and 6 of 43 (13.95%) positive anti-cardiolipin antibodies or lupus anti-coagulants, and 37 (41.11%) received hydroxychloroquine. Nineteen patients (21.11%) had pregnancy loss. Of 71 successful pregnancies, 28 (31.11%) infants were full-term, 42 (46.67%) pre-term and 1 (11.11%) post-term; 19 (26.39%) were small for gestational age (SGA), and 38 (52.58%) had low birth weight (LBW). Maternal complications occurred in 21 (23.33%) pregnancies [10 (11.11%) premature rupture of membrane (PROM), 8 (8.89%) pregnancy induced hypertension (PIH), 4 (4.44%) oligohydramnios, 2 (2.22%) post-partum hemorrhage, and 1 (1.11%) eclampsia]. Patients aged ≥ 25 years at pregnancy and those ever having renal involvement had predicted pregnancy loss with adjusted odds ratio (AOR) [95% CI] of 4.15 [1.10-15.72], P = .036 and 9.21 [1.03-82.51], P = .047, respectively. Renal involvement predicted prematurity (6.02 [1.77-20.52, P = .004), SGA (4.46 [1.44-13.78], P = .009), and LBW in infants (10.01 [3.07-32.62], P < .001). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception protected against prematurity (0.11 [0.02-0.85], P = .034). Flares and hematologic involvement predicted PROM (8.45 [1.58-45.30], P = .013) and PIH (9.24 [1.70-50.24], P = .010), respectively. Cutaneous vasculitis (33.87 [1.05-1,094.65], P = .047), and renal (31.89 [6.66-152.69], P < .001), mucocutaneous (9.17 [1.83-45.90], P = .007) and hematologic involvement (128.00 [4.60-3,564.46], P = .004) during pregnancy predicted flare; while prednisolone (>10 mg/day) and immunosuppressive drug use at conception reduced that risk (0.08 [0.01-0.68, P = .021).APOs remain a problem in Thai pregnant SLE patients. Renal involvement and SLE flares were associated with the risk of APOs.
1 Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ systems, characterized by remission and relapse. The disease predominantly affects women of child bearing age. Pregnancy in SLE patients is a challenging issue in clinical practice because of its association with increasing adverse outcomes in both mother and fetus.[1,2] Pregnant women with SLE have a reportedly higher rate of spontaneous abortion, fetal loss, intra-uterine growth retardation, pre-term delivery, pregnancy induced hypertension (PIH), pre-eclampsia and flares. Furthermore, pregnancy in SLE patients can cause disease exacerbation or flare, which often requires increasing doses of corticosteroids and/or immunosuppressive drugs that can have adverse effects on mother and fetus.[3,4] Thus, it is suggested that pregnancy in SLE patients should be avoided if the patients have had active severe disease within the previous 6 months, or significant heart, lung, renal and central nervous system involvement.[3,4]
With progress made in understanding the clinical course of SLE, standard instruments that determine disease activity and flares have been developed, as well as progression in medical treatment that results in improved obstetrics care of pregnant SLE patients.[3,5] Pregnancy outcomes in SLE patients have been reported widely, however, data on pregnancy outcomes from Asian countries are very limited.[6–11]
The purpose of this study was to determine pregnancy outcomes and identify independent predicting factors for adverse pregnancy outcomes (APOs) from a lupus cohort of Thai pregnant patients with SLE.
2 Patients and methods
2.1 Patients and data source
The medical records of SLE patients in a lupus cohort seen between January 1993 and June 2017 at the Division of Rheumatology, Faculty of Medicine, Chiang Mai University, Thailand were reviewed. SLE was diagnosed according to the 1997 updating the American College of Rheumatology (ACR) revised criteria for the classification of SLE.[12] Pregnant SLE patients were identified. Clinical manifestations, laboratory investigations, treatment, and SLE disease activity were recorded from 6 months prior to conception (−6 M) until 6 weeks after termination of pregnancy or delivery or the post-partum period. Pregnancy data were recorded at the time of conception or when the pregnancy was documented. The data were captured at −6 M, 3 months prior to conception (−3 M), at the time of conception, 1st trimester, 2nd trimester, 3rd trimester, and the post-partum period. If the patients had more than 1 visit during each period, the mean SLE disease activity of each period was used for statistical analysis. Laboratory investigations, including complete blood counts, urine analysis, and renal and liver functions were recorded routinely. The 24-hour urine protein creatinine ratio (24hour UPCI) [urine protein in gm/day to urine creatinine in gm/day] was determined only in cases with lupus nephritis (urine protein >0.5 gm/day). SLE patients were followed up usually in the clinic at 1 to 3 month intervals, depending on SLE disease activity or other clinical encounters. If the patients had more than 1 pregnancy, each one was considered as a separate observation and counted as an individual case.
Patients in the clinic should have been in clinical remission or have stable low disease activity (prednisolone ≤10 mg/day without immunosuppressive drugs other than anti-malarial medication) for a minimum of 12 months to allow for pregnancy to occur. Those who developed mild to moderate flares during pregnancy were administered prednisolone at a dosage of up to 0.50 mg/kg/day, and those with severe flares received >0.50 to 1.00 mg/kg/day. Anti-malarial medication was given according to clinical indications, e.g., skin rashes, oral ulcers or alopecia. Immunosuppressive drugs, particularly azathioprine and cyclosporine, were given to cases of severe flares. Cases in which the patients received methotrexate, cyclophosphamide or mycophenolate mofetil at the time of pregnancy, had these immunosuppressive drugs discontinued immediately and replaced with azathioprine or cyclosporine.
2.2 SLE disease activity and flare assessment
The modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K)[13] was used in this study to determine SLE disease activity (as anti-dsDNA and complements were not routinely available at this institution). The severity of SLE disease activity was classified according to that of Abrahamowicz et al,[14] but the mSLEDAI-2K instrument was used instead of the original SLEDAI-2K; remission [mSLEDAI-2K = 0], mild disease activity [mSLEDAI-2K = 1–5], moderate disease activity [mSLEDAI-2K = 6–10], high disease activity [mSLEDAI-2K = 11–19] and very high disease activity [mSLEDAI-2K = ≥20]). The severity of SLE flare (mild or moderate flare and severe flare) followed the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE flare index (SFI).[15] As the physician global assessment (PGA) was not recorded routinely, the SFI was modified by excluding the PGA items (mSFI). Organ damage accrual was determined using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).[16]
2.3 Pregnancy outcomes
The definition of maternal complications (premature rupture of membrane [PROM], oligohydramnios, pregnancy induced hypertension [PIH], pre-eclampsia, eclampsia, and direct and indirect maternal death), and fetal outcomes (pregnancy loss, miscarriage or spontaneous abortion, intra-uterine fetal death, medical termination of pregnancy, pre-term delivery, term delivery, post-term delivery, neonatal death, small for gestational age [SGA], and infant birth weight) followed that of standard references.[17]
2.4 Ethical statement
This study was performed in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This study was approved by the Ethic Committee of the Faculty of Medicine, Chiang Mai University (no. 215/2017).
2.5 Statistical analysis
STATA 14.2 computer software (Stata Corporation, Texas USA) was used for data processing and statistical analysis. As some patients had more than 1 pregnancy, each one was considered individually for statistical analysis. Continuous variables were presented as mean ± standard deviation (SD) or median (min-max), with categorical variables presented as percent. The Student t test and Wilcoxon rank sum test were used to determine the differences between 2 independent samples of continuous variables. One-way analysis of variance (ANOVA) and the Kruskal–Wallis test were used for more than 2 samples, with normal and non-normal distribution, respectively. The Chi-Squared test or Fisher exact test was used to determine associations among the categorical variables, where appropriate. Firth's logistic regression was used to predict the odds ratio (OR) and 95% confidence intervals (95% CI) when the outcome contained cell counts of zero. Variables with a P value <.20 from univariate analysis were entered into multiple logistic regression analysis, and reported as adjusted odds ratio (AOR) and 95% CI. A P ≤ .05 was considered as being a statistically significant difference.
3 Results
3.1 Demographics and characteristics of pregnant SLE patients
From a cohort of 1167 female SLE patients, 90 pregnancies occurred from 77 patients (1, 2, and 3 pregnancies in 66, 9 and 2 patients, respectively). Their mean age at SLE onset and age at pregnancy was 21.63 ± 5.89 years and 26.94 ± 4.80 years, respectively. Pregnancies occurred at the time of SLE diagnosis, and < 5 years and ≥ 5 years after SLE diagnosis in 7 (7.78%), 49 (54.44%) and 34 (37.78%) pregnancies, respectively. Of the 90 pregnancies, 45 (50.00%), 25 (27.78%), and 20 (22.22%) were the first, second and third or more, respectively. Their mean cumulative ACR classification criteria and SDI score were 5.49 ± 1.15 and 0.40 ± 0.72, respectively. The mean ± SD mSLEDAI-2K score at −6 M and time of conception was 1.72 ± 3.22 and 1.90 ± 3.44, respectively. Active disease at the time of conception (mSLEDAI-2K score ≥ 0) was observed in 33 of 90 pregnancies (36.67%), and all of them were unplanned. Active organ involvement at the time of conception was renal (urine protein creatinine ratio >0.5) in 20 (22.22%) pregnancies, mucocutaneous lesions in 15 (16.67%), cutaneous vasculitis in 2 (2.22%), and arthritis and hematologic abnormalities in 1 (1.11%) of each.
Co-morbidities were seen as follows: hypertension in 23 (25.56%) pregnancies, dyslipidemia in 8 (8.89%), thalassemia in 7 (7.78%), anti-phospholipid syndrome in 3 (3.33%), diabetes mellitus in 1 (1.11%), and others in 19 (21.11%) [hepatitis C virus infection, avascular necrosis of the hip, stroke and atrial secundum defect, and past history of cryptococcal meningitis, pneumocystis jirovecii pneumonia, and past treatment of pulmonary tuberculosis]. None of the patients drank alcohol or smoked.
Antinuclear antibodies (ANA) were observed in 89 pregnancies (98.89%). Anti-double stranded DNA (anti-dsDNA), anti-Smith (anti-Sm), anti-cardiolipin (ACL), lupus coagulants (LAC), and anti-Ro (anti-Ro) antibodies were observed in 50 of 85 (58.82%), 1 of 12 (8.33%), 4 of 58 (6.89%), 3 of 42 (7.14%), and 21 of 46 (45.65%) pregnancies that had been tested, respectively.
Patients in 15 of the 90 pregnancies (16.67%) had not received any specific SLE medication at the time of conception. Patients in 57 (63.33%) of the pregnancies received prednisolone at a dose of ≤10 mg/day, and in 16 (17.78%) at ≥ 10 mg/day, with the mean dosage of 10.77 ± 11.73 mg/day. Patients also received hydroxychloroquine (HCQ) in 37 (41.11%) pregnancies, cyclophosphamide in 6 (6.67%), mycophenolate mofetil in 4 (4.40%), azathioprine in 10 (11.11%), and cyclosporine in 3 (3.33%). Both cyclophosphamide and mycophenolate mofetil were switched to azathioprine or cyclosporine when the pregnancy was documented.
3.2 Overall pregnancy outcomes
Of the 90 pregnancies, 19 (21.11%) were lost (spontaneous abortion in 12 (13.33%) [7 in the 1st trimester and 5 in the 2nd], medical termination in 5 (5.56%) [1 in the 1st trimester and 4 in the 2nd], and dead fetus in the utero (1 in each 2nd and 3rd trimester). Of the 71 (78.89%) successful pregnancies, 28 (31.11%) were full-term, 42 (46.67%) pre-term (1 twin pregnancy), and 1 (1.11%) was a post-term delivery, resulting in 72 live born infants. Mode of delivery among the live births were vaginal in 52 (73.24%) and cesarean section in 19 (26.76%). The mean ± SD duration of pregnancy with live born infants was 35.76 ± 3.58 weeks. The mean ± SD weight of the 72 live born infants was 2,367.33 ± 640.30 gm (range 720–3853 gm), with normal birth weight (≥2500 gm), low birth weight (LBW) [1500–2499 gm], and very low birth weight (VLBW) [<1500 gm] in 34 (47.22%), 30 (41.67%) and 8 (11.11%) infants, respectively. SGA infants occurred in 19 live born infants (26.39%). There was 1 neonatal death (1.11%). No infants had congenital anomalies or completed heart block.
Maternal complications occurred in 21 (23.33%) pregnancies. PROM occurred in 10 (11.11%) pregnancies, PIH in 8 (8.89%), oligohydramnios in 4 (4.44%), post-partum hemorrhage in 2 (2.22%), and eclampsia in 1 (1.11%). One concomitant PROM and oligohydramnios, PROM and post-partum hemorrhage, PROM and PIH, and PIH and eclampsia occurred in each pregnancy. There were no cases of anti-partum hemorrhage, post-partum endometritis, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), pre-eclampsia or maternal death. Thirty seven flares (41.11%) were mild to moderate and severe in 9 (24.32%) and 28 (75.68%) pregnancies, respectively.
3.3 Effect of renal involvement, hypertension, presence of anti-cardiolipin antibodies and/or lupus anti-coagulants and SLE flares on pregnancy outcomes
The effects of renal involvement, hypertension, and the presence of ACL/LAC and SLE flares on pregnancy outcomes were determined and are shown in Table 1.
Table 1 Effect of active renal involvement during pregnancy, hypertension at the time of conception, presence of anti-phospholipid antibodies and SLE flares during pregnancy on pregnancy outcomes.
Renal involvement Hypertension ACL/LAC Flares
Yes No P value Yes No P value Yes No P value Yes No P value
Successful pregnancy, n (%) 30 (75.00) 41 (82.00) .419 16 (69.57) 55 (82.09) .204 4 (66.67) 32 (86.49) .248 32 (86.49) 39 (73.58) .140
Pregnancy duration, in weeks, mean ± SD 34.34 ± 4.50 36.80 ± 2.26 .009 35.60 ± 2.47 35.81 ± 3.86 .838 38.50 ± 2.52 36.20 ± 3.45 .209 34.43 ± 3.91 36.85 ± 2.90 .004
Fetal weight, in grams, mean ± SD 2,029.52 ± 611.82 2,622.76 ± 540.06 <.001 2,147.65 ± 580.34 2,435.24 ± 647.59 .106 2,680.00 ± 557.32 2,379.94 ± 749.66 .447 2097.58 ± 615.13 2595.59 ± 575.07 .001
Fetal outcomes
Live birth, n (%) 31 (75.61)∗ 41 (82.00) .456 17 (70.83)∗ 55 (82.09) .244 4 (66.67) 32 (86.49) .248 33 (86.84)∗ 39 (73.58) .125
Term, n (%) 6 (15.00) 22 (44.00) .003 7 (30.43) 21 (31.34) .935 3 (50.00) 14 (37.84) .666 9 (24.32) 19 (35.85) .245
Pre-term, n (%) 24 (58.54)∗ 19 (38.00) .051 10 (41.67)∗ 33 (49.25) .523 1 (16.67) 17 (45.95) .177 24 (63.16)∗ 19 (35.85) .010
Post-term, n (%) 1 (2.50) 0 .444 0 1 (1.49) >.999 0 1 (2.70) >.999 0 1 (1.89) >.999
Total fetal loss, n (%) 10 (25.00) 9 (18.00) .419 7 (30.43) 12 (17.91) .204 2 (33.33) 5 (13.51) .248 5 (13.51) 14 (26.42) .140
Spontaneous abortion, n (%) 6 (15.00) 6 (12.00) .677 4 (17.39) 8 (11.94) .507 1 (16.67) 4 (10.81) .547 3 (8.11) 9 (16.98) .223
Medical termination, n (%) 2 (5.00) 3 (6.00) >.999 2 (8.70) 3 (4.48) .599 1 (16.67) 1 (2.70) .262 1 (2.70) 4 (7.55) .645
Dead fetus in the utero, n (%) 2 (5.00) 0 .195 1 (4.35) 1 (1.49) .448 0 0 1 (2.70) 1 (1.89) >.999
Neonatal death, n (%) 1 (2.50) 0 .444 1 (4.35) 0 .256 0 1 (2.70) >.999 1 (2.70) 0 .411
SGA, n (%) 13 (32.50) 6 (12.00) .018 7 (30.43) 12 (17.91) .204 1 (16.67) 12 (32.43) .649 11 (29.73) 8 (15.09) .094
LBW (< 2500 grams), n (%) 25 (60.98)∗ 13 (26.00) .001 11 (45.83)∗ 27 (40.30) .637 1 (16.67) 18 (48.65) .143 23 (60.53)∗ 15 (28.30) .002
Maternal complications†, n (%) 30 (75.00) 15 (30.00) <.001 16 (69.57) 29 (43.28) .030 2 (33.33) 18 (48.65) .669 37 (100.00) 8 (15.09) <.001
PROM, n (%) 6 (15.00) 4 (8.00) .294 1 (4.35) 9 (13.43) .232 0 4 (10.81) >.999 8 (21.62) 2 (3.77) .008
Oligohydramnios, n (%) 3 (7.50) 1 (2.00) .319 1 (4.35) 3 (4.48) >.999 0 2 (5.41) >.999 2 (5.41) 2 (3.77) >.999
PPH, n (%) 0 2 (4.00) .501 0 2 (2.99) >.999 0 1 (2.70) >.999 0 2 (3.77) .510
PIH, n (%) 5 (12.50) 3 (6.00) .282 1 (4.35) 7 (10.45) .375 0 3 (8.11) >.999 5 (13.51) 3 (5.66) .198
Eclampsia, n (%) 0 1 (2.00) >.999 0 1 (1.49) >.999 0 1 (2.70) >.999 0 1 (1.89) >.999
Flares, n (%) 27 (67.50) 10 (20.00) <.001 14 (60.87) 23 (34.33) .026 2 (33.33) 14 (37.84) >.999
Forty pregnancies were shown to have active nephritis during pregnancy. Active renal involvement occurred in 30, 30, and 26 pregnancies during the 1st, 2nd, and 3rd trimester, respectively, which was significantly higher than the 20 pregnancies seen at the time of conception (P < .001). When compared to patients without renal involvement during pregnancy, those with it had significantly shorter mean pregnancy duration (34.34 ± 4.40 weeks vs 36.80 ± 2.26 weeks, P = .003), lower fetal birth weight among live births (2029.52 ± 611.82 gm vs 2622.76 ± 540.06 gm, P < .001), and a higher proportion of LBW infants (60.98% vs 26.00%, P < .001), and SGA infants (32.50% vs 12.00%, P = .018). Although the proportion among live birth infants was not different, those with renal involvement had a significantly lower proportion of full-term infants (15.00% vs 44.00%, P = .003) and almost significantly higher proportion of pre-term infants (58.54% vs 38.00%, P = .051). There was no statistically significant difference in fetal loss among the 2 groups. The maternal complications in those with renal involvement during pregnancy were significantly higher (75.00% vs 30.00%, P < .001), which was due to a higher proportion of patients with SLE flare (67.50% vs 20.00%, P < .001). Other maternal complications, including PROM, oligohydramnios and PIH, also were higher proportionally, but they did not reach statistical significance.
Overall, there were no statistically significant differences in adverse fetal outcomes among patients with or without hypertension during pregnancy. However, pregnancy outcomes among patients with hypertension tended to have a lower proportion of live birth infants, and higher proportion of fetal loss (both spontaneous and medical terminations), SGA and LBW among full-term infants, and a lower mean fetal birth weight. Maternal complications were significantly higher in patients with hypertension (69.57% vs 43.28%, P = .030), which was due mainly to the higher proportion of those with SLE flares (60.48% vs 34.33%, P = .026). It was interesting that the proportion of PROM and PIH was lower in patients with hypertension, but with no significance.
The effect of anti-cardiolipin antibodies (ACL) and lupus anticoagulant (LAC) tests on pregnancy outcomes also was determined. Unfortunately, these 2 tests were determined in only approximately 50% of the patients. ACA and LAC were positive in a small proportion of the patients (4 of 58 or 6.89% and 3 of 42 or 7.14% of those tested, respectively). Overall, there was no statistically significant difference between either the fetal and maternal outcomes among pregnant patients with positive ACL/LAC or those without; however, those with positive ACL/LAC tended to have a lower proportion of live births and full-term birth infants, and higher proportion of fetal losses. It was interesting that the proportion of SGA, LBW, and maternal complication in the ACL/LAC positive patients also was lower, but without statistical significance. This might be due to the small number of patients in this group.
The effect of flares on pregnancy outcomes also was determined. When compared to SLE patients without flares during pregnancy, those with them had significantly shorter duration of pregnancy (34.43 ± 3.91 weeks vs 36.85 ± 2.90 weeks, P = .004), and lower mean fetal weight among live births (2097.58 ± 615.13 gm vs 2595.59 ± 575.07 gm, P = .001). Although the proportion of live birth infants and fetal loss was no different between the 2 groups, the patients with flares had a significantly higher proportion of pre-term births and LBW infants (63.16% vs 35.85%, P = .010, and 60.53% vs 28.30%, P = .002, respectively). The proportion of SGA infants also was higher, but did not reach statistical significance (29.73% vs 15.09%, P = .094). The adverse maternal outcomes were higher (100.00% vs 15.09%, P < .001), particularly of PROM (21.62% vs 3.77%, P < .008).
3.4 Effect of HCQ used on pregnancy outcomes
The effect of HCQ used during pregnancy on pregnancy outcomes was determined. Overall, there was no statistically significant difference in fetal outcomes among patients who did or did not receive HCQ during pregnancy. However, infants born to mothers who used HCQ tended to have a higher proportion of full term births (37.84% vs 26.42%, P = .249), and lower proportion of SGA (16.22% vs. 24.53%, P = .342) and LBW (36.84% vs 45.28%, P = .421). The proportion of live birth infants and fetal loss was similar between the 2 groups (78.95% vs 79.25%, P = .972, and 21.62% vs. 20.75%, P = .921, respectively). The proportion of maternal complications was lower among patients who received HCQ, and it almost reached statistical significance (37.84% vs 58.49%, P = .054). The proportion of maternal PROM, PIH and flares in the HCQ group also was lower, but did not reach statistical significance (5.41% vs 15.09%, P = .150; 5.41% vs 11.32%, P = .332, and 32.43% vs 47.17%, P = .162, respectively).
3.5 Pregnancy outcomes according to period of pregnancy, and between the first and subsequence pregnancy
The pregnancy outcomes according to the period of pregnancy (1993–2001, 2002–2009, and 2010–2017) were determined. Overall, there was no statistically significant difference in fetal or maternal outcomes between each pregnancy period. However, when comparing the pregnancy outcomes between 2010–2017, 2002–2009, and 1993–2001, fetal outcomes among pregnancies during 2010–2017 tended to have a higher proportion of live births (80.85% vs 76.00% vs 78.95%, P = .890), full-term birth infants (36.17% vs 32.00% vs 16.67%, P = .313), but with a lower proportion of pre-term birth infants (42.55% vs 44.00% vs 63.16%, P = .294), and pregnancy loss (19.15% vs 24.00% vs 22.22%, P = .884). They also had had a higher proportion of SGA and LBW (29.79% vs 16.00% vs 5.56%, P = .070, and 48.94% vs 36.00% vs 31.58%, P = .342, respectively). The proportion of maternal complications was similar (48.94% vs 48.00% vs 55.56%, P = .868); but with a tendency for decreased proportion of PROM (8.51% vs 12.00% vs 16.67%, P = .495), PIH (8.51% vs 4.00% vs 16.67%, P = .382) and SLE flares (38.30% vs 44.00% vs 44.44%, P = .851).
The pregnancy outcomes between patients with a first pregnancy and subsequent pregnancies also were compared. Similarly, there was no significant difference in fetal and maternal outcomes between the 2 groups. However, fetal outcomes in subsequent pregnancy groups tended to have a lower proportion of live births (73.91% vs 84.44%, P = .217), full-term births (24.44% vs 37.78%, P = .172), SGA (17.78% vs 24.44%, P = .438) and LBW infants (36.96% vs 46.67%, P = .348), but higher proportion of fetal loss (26.67% vs 15.56%, P = .197). Maternal complications tended to be lower (46.67% vs 53.33%, P = .527), which was due mainly to decreased proportion of SLE flares (37.78% vs 44.44%, P = .520). The rate of caesarean section was significantly higher among subsequent pregnancies (39.39% vs 15.79%, P = .025).
3.6 Predicting factors for adverse pregnancy outcomes
In order to determine independent predicting factors for APOs, the clinical characteristics that associated with adverse fetal outcomes (pregnancy loss, prematurity, SGA and LBW), and adverse maternal outcomes (PROM, PIH and flare) were compared and are shown in Tables 2 and 3, respectively.
Table 2 Comparison of clinical characteristics of adverse fetal outcomes in pregnant SLE patients.
Successful pregnancy Pregnancy loss Pre-maturity Full term + post term SGA Non-SGA LBW Normal BW
Characteristics (n = 71) (n = 19) P value (n = 42) (n = 29) P value (n = 19) (n = 52) P value (n = 37) (n = 34) P value
Age at pregnancy (in years), mean ± SD 26.30 ± 4.55 29.31 ± 5.09 .014 26.46 ± 4.73 26.07 ± 4.34 .726 25.09 ± 3.85 26.74 ± 4.73 .178 26.12 ± 4.61 26.50 ± 4.54 .726
Disease duration prior to conception (in years), mean ± SD 4.92 ± 5.01 6.99 ± 5.37 .081 4.38 ± 3.96 5.71 ± 6.21 .574 5.20 ± 4.26 4.82 ± 5.29 .451 4.54 ± 4.08 5.34 ± 5.89 .954
Co-morbidities
Hypertension, n (%) 16 (22.54) 7 (36.84) .204 9 (21.43) 7 (24.14) .788 7 (36.84) 9 (17.31) .081 10 (27.03) 6 (17.65) .345
Diabetes, n (%) 1 (1.41) 0 >.999 1 (2.38) 0 >.999 1 (5.26) 0 .268 1 (2.70) 0 >.999
Dyslipidemia, n (%) 5 (7.04) 3 (15.79) .234 3 (7.14) 2 (6.90) >.999 4 (21.05) 1 (1.92) .016 4 (10.81) 1 (2.94) .359
APS, n (%) 2 (2.82) 1 (5.26) .513 0 2 (6.90) .163 0 2 (3.85) >.999 0 2 (5.88) .226
ANA positive, n (%) 70 (98.59) 19 (100.00) >.999 41 (97.62) 29 (100.00) >.999 19 (100.00) 51 (98.08) >.999 37 (100.00) 33 (97.06) .479
Anti-dsDNA, n (%)∗ 41/67 (61.19) 9/18 (50.00) .392 26/40 (65.00) 15/27 (55.56) .436 13/19 (68.42) 28/48 (58.33) .445 25/37 (67.57) 16/30 (53.33) .234
Anti-Sm, n (%)∗ 0/11 1/1 (100.00) .083 0/7 0/4 0/2 0/9 0/6 0/5
ACL/LAC, n (%)∗ 4/36 (11.11) 2/7 (28.57) .248 1/18 (5.56) 3/18 (16.67) .603 1/13 (7.69) 3/23 (13.04) >.999 1/19 (5.26) 3/17 (17.65) .326
Anti-Ro, n (%)∗ 16/38 (42.11) 5/8 (62.50) .293 7/17 (41.18) 9/21 (42.86) .917 6/13 (46.15) 10/25 (40.00) .715 11/23 (47.83) 5/15 (33.33) .376
Anti-La, n (%)∗ 16/38 (42.11) 4/9 (44.44) .898 7/17 (41.18) 9/21 (42.86) .917 6/13 (46.15) 10/25 (40.00) .715 11/23 (47.83) 5/15 (33.33) .376
Pregnancy loss (ever), n (%) 23 (32.39) 9 (47.37) .226 12 (28.57) 11 (37.93) .407 6 (31.58) 17 (32.69) .929 11 (29.73) 12 (35.29) .617
Cumulative number of ACR criteria, mean ± SD 5.46 ± 1.11 5.58 ± 1.35 .704 5.38 ± 1.17 5.59 ± 1.02 .446 5.42 ± 1.02 5.48 ± 1.15 .842 5.35 ± 1.06 5.59 ± 1.16 .371
Disease activity (mSLEDAI-2K) at −6M, mean ± SD 1.34 ± 2.43 3.16 ± 5.05 .325 1.36 ± 2.44 1.31 ± 2.46 .960 1.42 ± 2.48 1.31 ± 2.44 .874 1.38 ± 2.53 1.29 ± 2.36 .933
Disease activity (mSLEDAI-2K) at conception, mean ± SD 1.58 ± 2.74 3.16 ± 5.22 .562 1.81 ± 2.98 1.24 ± 2.36 .385 2.16 ± 2.99 1.36 ± 2.64 .222 1.92 ± 3.22 1.20 ± 2.08 .566
Remission, n (%) 45 (63.38) 12 (63.16) .321 25 (59.52) 20 (68.97) .629 10 (52.63) 35 (67.31) .444 23 (62.16) 22 (64.71) .955
Mild, n (%) 19 (26.76) 3 (15.79) 13 (30.95) 6 (20.69) 6 (31.58) 13 (25.00) 10 (27.03) 9 (26.47)
Moderate and high, n (%) 7 (9.86) 4 (21.05) 4 (9.52) 3 (10.34) 3 (15.79) 4 (7.69) 4 (10.81) 3 (8.82)
SDI score at conception, mean ± SD 0.35 ± 0.66 0.58 ± 0.90 .400 0.36 ± 0.62 0.34 ± 0.72 .612 0.21 ± 0.42 0.40 ± 0.72 .463 0.24 ± 0.55 0.47 ± 0.75 .169
Active organ involvement during pregnancy
Renal 30 (42.25) 10 (52.63) .419 23 (54.76) 7 (24.14) .010 13 (68.42) 17 (32.69) .007 24 (64.86) 6 (17.65) <.001
Mucocutaneous 23 (32.39) 4 (21.05) .338 12 (28.57) 11 (37.93) .407 4 (21.05) 19 (36.54) .217 9 (24.32) 14 (41.18) .130
Vasculitis 2 (2.82) 1 (5.26) .513 1 (2.38) 1 (3.45) >.999 1 (5.26) 1 (1.92) .466 1 (2.70) 1 (2.94) >.999
Arthritis 2 (2.82) 0 >.999 2 (4.76) 0 .510 0 2 (3.85) >.999 1 (2.70) 1 (2.94) >.999
Hematologic 8 (11.27) 0 .125 6 (14.29) 2 (6.90) .333 4 (21.05) 4 (7.69) .197 5 (13.51) 3 (8.82) .532
Medication at conception
Prednisolone, n (%) 56 (78.87) 17 (89.47) .294 32 (76.19) 24 (82.76) .505 15 (78.95) 41 (78.85) .993 31 (83.78) 25 (73.53) .290
Dose (in mg/day), mean ± SD 9.11 ± 9.38 16.25 ± 16.58 .058 9.53 ± 9.56 8.54 ± 9.32 .412 12.50 ± 12.32 7.86 ± 7.88 .162 9.11 ± 9.39 9.10 ± 9.57 .823
Prednisolone >10 mg/day 10 (14.08) 6 (31.58) .076 6 (14.29) 4 (13.79) .953 5 (26.32) 5 (9.62) .073 6 (16.22) 4 (11.76) .590
Hydroxychloroquine, n (%) 29 (40.85) 8 (42.11) .921 15 (35.71) 14 (48.28) .290 6 (31.58) 23 (44.23) .337 13 (35.14) 16 (47.06) .307
Dose (in mg/day), mean ± SD 191.38 ± 86.67 256.25 ± 129.39 .144 183.33 ± 79.43 200.00 ± 96.08 .762 166.67 ± 51.64 197.83 ± 93.52 .533 165.38 ± 55.47 212.50 ± 102.47 .275
Immunosuppressive drug† 18 (25.35) 4 (21.05) .699 10 (23.81) 8 (27.59) .719 5 (26.32) 13 (25.00) .910 12 (32.43) 6 (17.65) .153
Mycophenolate mofetil, n (%) 4 (5.63) 0 .575 2 (4.76) 2 (6.90) >.999 1 (5.26) 3 (5.77) >.999 3 (8.11) 1 (2.94) .615
Cyclophosphamide, n (%) 3 (4.23) 3 (15.79) .106 3 (7.14) 0 .265 1 (5.26) 2 (3.85) >.999 3 (8.11) 0 .241
Azathioprine, n (%) 10 (14.08) 0 .083 5 (11.90) 5 (17.24) .525 3 (15.79) 7 (13.46) .803 6 (16.22) 4 (11.76) .590
Cyclosporine, n (%) 2 (2.82) 1 (5.26) .513 0 2 (6.90) .163 0 2 (3.85) >.999 1 (2.70) 1 (2.94) >.999
Flare during pregnancy 32 (45.07) 5 (26.32) .140 23 (54.76) 9 (31.03) .048 11 (57.89) 21 (40.38) .189 22 (59.46) 10 (29.41) .011
Table 3 Comparison of clinical characteristics of adverse maternal outcomes in pregnant SLE patients.
Premature rupture of membrane Pregnancy induced hypertension Flares
Characteristics Yes (n = 10) No (n = 80) P value Yes (n = 8) No (n = 82) P value Yes (n = 37) No (n = 53) P value
Age at pregnancy (in years), mean ± SD 28.85 ± 4.38 26.70 ± 4.82 .182 25.92 ± 3.65 27.03 ± 4.90 .535 26.89 ± 4.75 26.97 ± 4.88 .937
Disease duration prior to conception (in years), mean ± SD 3.81 ± 3.06 5.55 ± 5.31 .521 4.67 ± 6.25 5.43 ± 5.04 .257 5.67 ± 5.45 5.14 ± 4.92 .608
Co-morbidities
Hypertension, n (%) 1 (10.00) 22 (27.50) .232 1 (12.50) 22 (26.83) .375 14 (37.84) 9 (16.98) .026
Diabetes, n (%) 0 1 (1.25) >.999 0 1 (1.22) >.999 0 1 (1.89) >.999
Dyslipidemia, n (%) 0 8 (10.00) .295 0 8 (9.76) .355 3 (8.11) 5 (9.43) .828
APS, n (%) 0 3 (3.75) >.999 0 3 (3.66) >.999 2 (5.41) 1 (1.89) .566
ANA positive, n (%) 10 (100.00) 79 (98.75) >.999 7 (87.50) 82 (100.00) .089 37 (100.00) 52 (98.11) >.999
Anti-dsDNA, n (%)∗ 5/9 (55.56) 45/76 (59.21) .833 5/7 (71.43) 45/78 (57.69) .479 20/35 (57.14) 30/50 (60.00) .792
Anti-Sm, n (%)∗ 0/1 1/11 (9.09) >.999 0/1 1/11 (9.09) >.999 0/4 1/8 (12.50) >.999
ACL/LAC, n (%)∗ 0/4 6/39 (15.38) >.999 0/3 6/40 (15.00) >.999 2/16 (12.50) 4/27 (14.81) >.999
Anti-Ro, n (%)∗ 1/4 (25.00) 20/42 (47.62) .614 2/4 (50.00) 19/42 (45.24) >.999 6/15 (40.00) 15/31 (48.39) .592
Anti-La, n (%)∗ 1/4 (25.00) 19/43 (44.19) .626 2/4 (50.00) 18/43 (41.86) >.999 6/15 (40.00) 14/32 (43.75) .808
Pregnancy loss (ever), n (%) 3 (30.00) 29 (36.25) .697 2 (25.00) 30 (36.59) .513 9 (24.32) 23 (43.40) .063
Cumulative number of ACR criteria, mean ± SD 5.30 ± 1.06 5.51 ± 1.17 0.586 5.62 ± 0.52 5.48 ± 1.20 .518 5.54 ± 1.14 5.45 ± 1.17 .725
Disease activity (mSLEDAI-2K) at -6M, mean ± SD 0.40 ± 1.26 1.89 ± 3.35 .116 0.25 ± 0.71 1.86 ± 3.33 .163 1.70 ± 3.44 1.74 ± 3.09 .696
Disease activity (mSLEDAI-2K) at conception, mean ± SD 0.70 ± 1.34 2.06 ± 3.59 .400 1.00 ± 2.14 2.00 ± 3.54 .454 2.16 ± 3.92 1.74 ± 3.09 .624
Remission, n (%) 7 (70.00) 50 (62.50) 0.450 6 (75.00) 51 (62.20) .704 22 (59.46) 35 (66.04) 0.816
Mild, n (%) 3 (30.00) 19 (23.75) 1 (12.50) 21 (25.61) 10 (27.03) 12 (22.64)
Moderate and high, n (%) 0 11 (13.75) 1 (12.50) 10 (12.20) 5 (13.51) 6 (11.32)
SDI score at conception, mean ± SD 0.50 ± 0.85 0.39 ± 0.70 .728 0 ± 0 0.44 ± 0.74 .079 0.54 ± 0.80 0.30 ± 0.64 .120
Active organ involvement during pregnancy
Renal 6 (60.00) 34 (42.50) .294 5 (62.50) 35 (42.68) .282 27 (72.97) 13 (24.53) <.001
Mucocutaneous 4 (40.00) 23 (28.75) .464 4 (50.00) 23 (28.05) .234 17 (45.95) 10 (18.87) .006
Vasculitis 0 3 (3.75) >.999 0 3 (3.66) >.999 3 (8.11) 0 .066
Arthritis 0 2 (2.50) >.999 0 2 (2.44) >.999 1 (2.70) 1 (1.89) >.999
Hematologic 2 (20.00) 6 (7.50) .190 3 (37.50) 5 (6.10) .003 8 (21.62) 0 <.001
Medication at conception
Prednisolone, n (%) 8 (80.00) 65 (81.25) .924 4 (50.00) 69 (84.15) .039 29 (78.38) 44 (83.02) .580
Dose (in mg/day), mean ± SD 5.94 ± 2.65 11.36 ± 12.78 .423 19.38 ± 27.26 10.27 ± 10.41 .755 8.88 ± 7.89 12.02 ± 13.63 .958
Prednisolone >10 mg/day 0 16 (20.00) .119 1 (12.50) 15 (18.29) .683 5 (13.51) 11 (20.75) .377
Hydroxychloroquine, n (%) 2 (20.00) 35 (43.75) .150 2 (25.00) 35 (42.68) .332 12 (32.43) 25 (47.17) .162
Dose (in mg/day), mean ± SD 125.00 ± 106.07 210.00 ± 98.37 .223 150.00 ± 70.71 208.57 ± 100.36 .382 208.33 ± 129.39 204.00 ± 84.06 .797
Immunosuppressive drug† 2 (20.00) 20 (25.00) .729 0 22 (26.83) .092 7 (18.92) 15 (28.30) .308
Mycophenolate mofetil, n (%) 1 (10.00) 3 (3.75) .381 0 4 (4.88) >.999 2 (5.41) 2 (3.77) >.999
Cyclophosphamide, n (%) 0 6 (7.50) .370 0 6 (7.32) .428 1 (2.70) 5 (9.43) .208
Azathioprine, n (%) 1 (10.00) 9 (11.25) .906 0 10 (12.20) .295 4 (10.81) 6 (11.32) .940
Cyclosporine, n (%) 0 3 (3.75) >.999 0 3 (3.66) >.999 0 3 (5.66) .266
Flare during pregnancy 8 (80.00) 29 (36.25) .008 5 (62.50) 32 (39.02) .198
Factors that might be associated with adverse fetal and maternal outcomes, and those that had a statistical difference with a P value of <.2 in the univariate analysis (Tables 2 and 3) were included in the multiple logistic regression analysis (Tables 4 and 5). Independent predicting factors that increased the risk of fetal loss included age at pregnancy of ≥25 years (AOR [95% CI]) 4.15 [1.10–15.72], P = .036), and ever having renal involvement (9.21 [1.03–82.51], P = .047). Prednisolone used (>10 mg/day) at conception almost reached a predicting factor for fetal loss (3.89 [0.99–15.20], P = .051). Renal involvement during pregnancy independently predicted prematurity (6.02 [1.77–20.52], P = .004), and SGA (4.46 [1.44–13.78], P = .009) and LBW infants (10.01 [3.07–32.62], P < .001). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception independently reduced the risk of prematurity (0.11 [0.02–0.85], P = .034). SLE flares and hematologic involvement during pregnancy independently predicted PROM (8.45 [1.58–45.30], P = .013) and PIH (9.24 [1.70–50.24], P = .010), respectively. Independent predicting factors for SLE flares during pregnancy included the presence of cutaneous vasculitis (AOR [95% CI]) 33.87 [1.05–1094.65], P = .047), and renal (31.89 [6.66–152.69], P < .001), mucocutaneous (9.17 [1.83–45.90], P = .007) and hematologic involvement (128.00 [4.60–3,564.46], P = .004). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception independently reduced the risk of SLE flares during pregnancy (0.08 [0.01–0.68, P = .021).
Table 4 Univariable analysis and multiple logistic regression analysis of factors associated with adverse fetal outcomes in pregnant SLE patients.
Pregnancy loss Prematurity Small for gestational age Low birth weight
Characteristics N1 n OR (95% CI) P value N2 n OR (95% CI) P value n OR (95% CI) P value n OR (95% CI) P value
Age at pregnancy
<25 years 39 4 3.64 35 21 0.93 13 0.34 19 0.84
≥25 years 51 15 (1.01–16.37) .027a 36 21 (0.32–2.67) .886 6 (0.09–1.16) .051 18 (0.30–2.37) .718
Disease duration prior to conception
<5 years 56 8 2.87 48 28 1.11 13 0.95 26 0.78
≥5 years 34 11 (0.90–9.34) .042 23 14 (0.36–3.52) .839 6 (0.25–3.28) .929 11 (0.25–2.36) .617
Hypertension
No 67 12 2.00 55 33 0.86 12 2.79 27 1.73
Yes 23 7 (0.56–6.64) .204 16 9 (0.24–3.15) .788 7 (0.71–10.44) .081 10 (0.48–6.59) .345
Previous pregnancy
0 45 7 1.97 38 21 1.42 11 0.78 21 0.76
≥1 45 12 (0.62–6.61) .196 33 21 (0.49–4.12) .474 8 (0.23–2.56) .655 16 (0.27–2.15) .568
Pregnancy loss (ever)
No 58 10 1.88 48 30 0.65 13 0.95 26 0.78
Yes 32 9 (0.58–5.92) .226 23 12 (0.21–2.03) .408 6 (0.25–3.28) .929 11 (0.25–2.36) .617
Renal disorder (ever)
No 18 1 5.67 17 6 3.67 3 1.96 5 3.49
Yes 72 18 (0.76–249.73) .071b 54 36 (1.02–13.92) .022 16 (0.45–12.00) .330 32 (0.96–14.27) .032
SLE disease activity at conception
Remission and mild 79 15 2.44 64 38 0.91 16 2.25 33 1.25
Moderate and high 11 4 (0.46–11.06) .186 7 4 (0.14–6.76) .909 3 (0.29–14.72) .311 4 (0.19–9.22) .779
Prednisolone >10 mg/day at conception
No 74 13 2.82 61 36 1.04 14 3.36 31 1.45
Yes 16 6 (0.70–10.38) .076c 10 6 (0.22–5.55) .953 5 (0.66–16.66) .073 6 (0.31–7.68) .590
IM drugs used at conception
No 68 15 0.78 53 32 0.82 14 1.07 25 2.24
Yes 22 4 (0.17–2.93) .699 18 10 (0.24–2.83) .719 5 (0.25–3.99) .910 12 (0.65–8.33) .152
Prednisolone >10 mg/day and IM drugs used at conception
No 82 17 1.27 65 40 0.31 17 1.41 34 0.91
Yes 8 2 (0.12–7.98) .778 6 2 (0.03–2.40) .179d 2 (0.12–10.86) .704 3 (0.11–7.33) .914
HCQ used during pregnancy
No 47 11 0.75 36 23 0.67 11 0.67 21 0.60
Yes 43 8 (0.23–2.33) .577 35 19 (0.23–1.93) .410 8 (0.20–2.20) .464 16 (0.21–1.70) .287
Organ involvement during Pregnancy
Cutaneous vasculitis
No 87 18 1.92 69 41 0.68 18 2.83 36 0.92
Yes 3 1 (0.03–38.45) .598 2 1 (0.01–55.50) .789 1 (0.03–226.66) .451 1 (0.01–74.11) .952
Arthritis
No 88 19 0.71 69 40 3.64 19 0.52 36 0.92
Yes 2 0 (0.03–15.47) .829 2 2 (0.17–78.70) .410 0 (0.02–11.28) .676 1 (0.01–74.11) .952
Renal
No 50 9 1.52 41 19 3.80 6 4.46 13 8.62
Yes 40 10 (0.48–4.78) .419 30 23 (1.21–12.72) .010e 13 (1.28–16.62) .007f 24 (2.54–31.31) <.001g
Mucocutaneous
No 63 15 0.56 48 30 0.65 15 0.46 28 0.46
Yes 27 4 (0.12–2.03) .338 23 12 (0.21–2.03) .408 4 (0.10–1.76) .217 9 (0.14–1.42) .130
Hematologic
No 82 19 0.19 63 36 2.25 15 3.20 32 1.61
Yes 8 0 (0.01–3.47) .264 8 6 (0.36–24.23) .333 4 (0.52–19.11) .115 5 (0.28–11.21) .532
Flares during pregnancy
No 53 14 0.44 39 19 2.69 8 2.03 15 3.52
Yes 37 5 (0.11–1.47) .140 32 23 (0.90–8.28) .048 11 (0.62–6.84) .189 22 (1.18–10.70) .011
Table 5 Univariable analysis and multiple logistic regression analysis of factors associated with adverse maternal outcomes in pregnant SLE patients.
Premature rupture of the membrane Pregnancy induced hypertension Flares
Characteristics N n OR 95% CI P value n OR 95% CI P value n OR 95% CI P value
Age at pregnancy
<25 years 39 2 Ref. 4 Ref. 18 Ref.
≥25 years 51 8 3.44 0.62–34.83 .114 4 0.74 0.13–4.31 .690 19 0.69 (0.27–1.76) .395
Disease duration prior to conception
<5 years 56 7 Ref. 6 Ref. 22 Ref.
≥5 years 34 3 0.68 0.10–3.25 .590 2 0.52 0.05–3.17 .435 15 1.22 (0.47–3.15) .652
Hypertension
No 67 9 Ref. 7 Ref. 23 Ref.
Yes 23 1 0.29 0.01–2.36 .232 1 0.39 0.01–3.35 .375 14 2.98 (1.01–8.99) .026
Previous pregnancy
0 45 4 Ref. 4 Ref. 20 Ref.
≥1 45 6 1.58 0.34–8.16 .502 4 1.00 0.17–5.76 >.999 17 0.76 (0.30–1.91) .520
Pregnancy loss (ever)
No 58 7 Ref. 6 Ref. 28 Ref.
Yes 32 3 0.75 0.12–3.63 .697 2 0.58 0.05–3.52 .514 9 0.42 (0.14–1.15) .063
Renal disorder (ever)
No 18 1 Ref. 0 Ref. 5 Ref.
Yes 72 9 2.43 0.30–112.60 .402 8 4.88 0.27–88.50 .284 32 2.08 (0.61–8.19) .199
SLE disease activity at conception
Remission and mild 79 10 Ref. 7 Ref. 32 Ref.
Moderate and high 11 0 0.29 0.02–5.26 .401 1 1.03 0.02–9.54 .980 5 1.22 (0.27–5.27) .755
Prednisolone >10 mg/day at conception
No 74 10 Ref. 7 Ref. 32 Ref.
Yes 16 0 0.19 0.01–3.34 .254 1 0.64 0.01–5.64 .682 5 0.60 (0.15–2.11) .377
IM drugs used at conception
No 68 8 Ref. 8 Ref. 30 Ref.
Yes 22 2 0.75 0.07–4.22 .729 0 0.16 0.01–2.85 .212 7 0.59 (0.18–1.79) .308
Prednisolone >10 mg/day and IM drugs used at conception
No 82 10 Ref. 8 Ref. 36 Ref.
Yes 8 0 0.41 0.02–7.57 .546 0 0.52 0.03–9.74 .659 1 0.18 (0.00–1.55) .085c
HCQ used during pregnancy
No 47 8 Ref. 5 Ref. 20 Ref.
Yes 43 2 0.24 0.02–1.31 .062 3 0.63 0.09–3.50 .542 17 0.88 (0.35–2.22) .771
Organ involvement during pregnancy
Cutaneous vasculitis
No 87 10 Ref. 8 Ref. 34 Ref.
Yes 3 0 1.05 0.05–21.88 .973 0 1.34 0.06–28.11 .852 3 10.86 (0.54–216.71) .119d
Arthritis
No 88 10 Ref. 8 Ref. 36 Ref.
Yes 2 0 1.50 0.07–33.32 .799 0 1.89 0.08–42.79 .688 1 1.44 (0.02–115.53) .796
Renal
No 50 4 Ref. 3 Ref. 10 Ref.
Yes 40 6 2.03 0.44–10.49 .294 5 2.24 0.40–15.24 .282 27 8.31 (2.90–24.34) <.001e
Mucocutaneous
No 63 6 Ref. 4 Ref. 20 Ref.
Yes 27 4 1.65 0.31–7.69 .464 4 2.56 0.43–14.84 .196 17 3.66 (1.29–10.54) .006f
Hematologic
No 82 8 Ref. 5 Ref. 29 Ref.
Yes 8 2 3.08 0.26–21.22 .190 3 9.24 1.07–64.46 .003b 8 30.83 (1.72–553.28) .020g
Flares during pregnancy
No 53 2 Ref. 3 Ref.
Yes 37 8 7.03 1.26–70.80 .008a 5 2.60 0.46–17.73 .198
4 Discussion
Despite significant improvement in medical care for pregnant SLE patients, their APOs are still a significant issue.[5,18] Fetal loss (both spontaneous abortion and intra-uterine death), pre-term birth, intra-uterine growth retardation, SGA and LBW in the fetus, and PIH, pre-eclampsia/eclampsia and flares in the mother are among the major APOs of concern. Reports on SLE patients with APOs varied greatly among studies. This could be explain partly by the difference in time period of the study and ethnicity and socioeconomic status of the patients, as well as SLE disease activity prior to and at the time of conception, organ involvement at conception, rate and organ of flares, and prevalence of ACL/LAC or anti-phospholipid syndrome in the population studied.[1,3,19]
Progressive improvement in pregnancy outcomes over a 25-year period was observed in this study. The proportion of successful pregnancies tended to improve with an increased proportion of full-term births and decreased proportion of pre-term infants. An increased proportion of infants with SGA and LBW had slightly decreased mean fetal birth weight; although all of these changes did not reach statistical significance. The improvement in pregnancy outcomes in Thai SLE patients was similar overtime to that in many previous reports.[5,18,20,21] However, the reason for the increased frequency of SGA and LBW was not clear, despite more frequent full-term birth infants.
This study also found that pregnancy outcomes of subsequent pregnancies in SLE patients showed a slightly decreased proportion of live births, full-term births, and SGA and LBW infants, but with slightly increased proportion of fetal loss, particularly among medical terminations. The lower proportion of SGA and LBW in the subsequent pregnancies in this study was similar to that of Wallanius et al,[22] but different from that of Korese et al,[23] who found that the fetal and maternal outcomes were almost similar between the first and subsequent pregnancies, except for the latter having slightly lower pre-term births. Reasons for the higher proportion of medical terminations in subsequent pregnancies in this study were not clear, but this might have been due to decisions made by the mothers and physicians, who were afraid of severe maternal or fetal complications if the pregnancy continued, and the patients probably had a baby already from the previous pregnancy. The proportion of cesarean section delivery among the subsequent pregnancies in this study was significantly (approximately 2 times) higher than that in the first pregnancy, which was similar to that reported by Wallenius et al.[22] This could be explained by the perception of the patients and physicians in that they were afraid of possible uterine rupture during delivery.
The PIH and eclampsia prevalence of 8.89% and 1.11%, respectively, in this study was in line with many previous reports that showed prevalence of 0–19% and 0–20% for PIH[20,23–27] and pre-eclampsia, respectively[20,23–27]. However, when looking at details, studies with a high incidence of PIH had a rather low incidence of pre-eclampsia or vise-versa; except for that reported by Wu et al,[27] and Kroese et al.[23] The reason for the discordance among these reports was unclear. It is not easy in clinical practice to differentiate between PIH and pre-eclampsia in pregnant patients with pre-existing hypertension and renal disease, as hypertension is an important clinical feature in both conditions. For example, a patient with pre-existing hypertension and some degree of proteinuria has slightly increasing proteinuria (without blood cells or cellular casts in the urine, with decreasing complement level, or increasing anti-dsDNA), and elevated blood pressure in the late course of pregnancy. In this situation, many physicians might consider PIH, while others consider pre-eclampsia. A definite diagnosis of these 2 conditions probably can be made only upon patient follow-up of the patients whether both hypertension and proteinuria are resolved or returned to baseline level prior to the development of hypertension and increasing proteinuria during the post-partum period. There were no pre-eclampsia cases in this study. As patients with increasing hypertension and slightly increasing proteinuria without active urine sediment had their blood pressure, but not the proteinuria, returned to normal or baseline during the post-partum period. These patients were considered to have PIH and not pre-eclampsia.
Similar to the differentiation between PIH and pre-eclampsia, differentiation between pre-eclampsia and active nephritis flare is another challenging issue in clinical practice. Several reviews suggest that the presence of extra-renal manifestation, past history of lupus nephritis, presence of or increasing proteinuria at the early trimester of pregnancy, presence of new hypertension onset, presence of active urinary sediments, decreasing serum complement levels, increasing anti-dsDNA levels and normal serum uric acid, favor active nephritis. However, if the aforementioned conditions occur late in the pregnancy, and the patient does not have decreasing complement or increasing anti-dsDNA levels, differential diagnosis between active nephritis and pre-eclampsia would be more difficult.[28–30] The situation would be more complicated if the patient has underlying hypertension prior to pregnancy or slight proteinuria prior to conception. Furthermore, these 2 conditions can co-exist in the same patients.[31] Some authors have suggested performing a kidney biopsy in the latter condition,[29,32] as the management of active lupus nephritis and pre-eclampsia is different. Again, sometimes the diagnosis can be made only upon delivery of the fetus when the above conditions disappear or return to normal.[3] All of the patients who had significantly increasing proteinuria in this study also had active urine sediment, and the degree of proteinuria did not return to normal or baseline at the end of the post-partum period. All of them also showed renal response to an increasing dose of corticosteroid and immunosuppressive drugs, therefore, they were more likely to have active nephritis flare rather than pre-eclampsia.
The pathogenic mechanisms of PIH and pre-eclampsia are not clear, but have been reviewed widely, and included innate immunity,[33] bioactive factors (such as inflammatory cytokines, angiogenetic factors, growth factors, etc.),[34,35] oxidative stress,[36] placental vascular maladaptation,[37] and endothelial dysfunction.[38,39] Among these, endothelial dysfunction is the most likely underlying mechanism,[39] which causes imbalance between an endothelial-derived vasodilator (such as nitric oxide and prostacyclin) and vasoconstrictors (such as endothelin-1, thromboxane A2), leading to the promotion of vasoconstriction, hypertension, and pre-eclampsia. Placenta ischemia stimulates the release of several bioactive factors and inflammatory cytokines that target the endothelial cells that lead to generalized endothelial cell dysfunction, which in turn causes vascular remodeling, increased arterial stiffness, and hypertension. Current treatment options of pre-eclampsia are limited. Only low dose aspirin has been shown as effective and is recommended by several international obstetrics and gynecologists guidelines for use in preventing pre-eclampsia in high risk patients.[40] Unfortunately, the effect of low dose aspirin on pregnancy outcomes was not determined in this study.
The effect of HCQ use on pregnancy outcomes also has been of interest in lupus pregnancy, although many previous studies could not find a significant difference in overall SLE pregnancy outcomes between HCQ users and non-users.[41–43] However, some studies showed some beneficial effects of HCQ use during pregnancy, including lower rate of fetal loss and pre-term births,[20,44] intra-uterine growth restriction (IUGR) in the fetus,[44] longer duration of pregnancy,[42] flare prevention,[43,45] and decreased PIH.[46] Although no significant difference in APOs among HCQ users and non-users was demonstrated in this study, there tended to be fewer maternal complications among HCQ users, particularly in a lower proportion of PROM, PIH and SLE flares.
Several factors have been identified in association with APOs in pregnant patients with SLE. These have included the presence of renal involvement or active nephritis,[20,24,47–53] SLE flares during pregnancy,[7,24,50,53,54] active disease prior to or during pregnancy,[20,50,54–56] hypertension,[7,24,25,54–57] presence of anti-phospholipid antibodies (APL) and/or lupus anti-coagulants,[7,20,23,24,50,53,54,56,57] cytopenia,[41,50,52,54] and hypocomplementemia.[20,25,50,54,56,58,59] This study also confirmed that renal involvement during pregnancy was associated with poor pregnancy outcomes, in both the fetus and mother. However, the presence of hypertension only associated with maternal flares.
Although APOs have been reported in several studies, only a few identified independent predicting factors for adverse fetal and maternal outcomes. In addition, the results of these predicting factors also were inconsistent. For example, Cortes-Hernandez et al[25] found that the presence of ACL and hypertension during pregnancy were independent predicting factors for poor fetal outcomes, whereas the presence of anti-β2-glycoprotein-1, hypertension at conception and hypocomplemetemia were independent predicting factors for fetal loss. Kwok et al[24] found that hypertension was an independent predicting factor for fetal loss, nephritis for SGA, low serum albumin for IUGR and SLE flares for prematurity among infants; and nephritis was an independent predicting factor for SLE flares, and hypertension and high disease activity for pre-eclampsia among mothers. Ko et al[26] found that the presence of APL antibodies was an independent predicting factor for fetal loss and pre-term births, and active disease for pre-term births. Active SLE and SLE flares were independent predicting factors for PIH and IUGR among mothers. Buyon et al[41] found that the presence of LAC, hypertension, high disease activity, maternal flares, and thrombocytopenia were predictors of APOs. Lui et al[60] found that pre-eclampsia/eclampsia and thrombocytopenia were independent predicting factors for fetal loss and SLE flares in mothers. Pre-eclampsia/eclampsia also was an independent predicting factor for pre-term birth among infants. Borella et al[56] found that hypertension was an independent predicting factor for fetal loss, miscarriage and SGA, and anti-phospholipid syndrome (APS) for prematurity in infants; whereas LAC was an independent predicting factor for pre-eclampsia, and active disease at −6 M for PROM. Kalok et al[6] found that SLE flares and active disease were predicting factors for fetal loss and pre-term birth, and also SLE flares for SGA among infants. Active SLE was an independent predicting factor for SLE flares and lupus nephritis, while SLE flares and the presence of APL antibodies were independent predicting factors for pre-eclampsia among mothers. Wu et al[59] recently found that unplanned pregnancy, hypocomplementemia and urine protein >1.0 gm/day were independent predicting factors for fetal loss. This study found that age >25 years and ever having renal involvement were independent predicting factors for fetal loss, renal involvement during pregnancy, prematurity, SGA and LBW among infants. SLE flare during pregnancy and hematologic involvement were independent predicting factors for PROM and PIH, respectively, among mothers. It was interesting that the use of prednisolone (>10 mg/day) and immunosuppressive drugs at conception was an independent protecting factor for prematurity. The presence of cutaneous vasculitis, and renal, mucocutaneous and hematologic involvement during pregnancy was an independent predicting factor for SLE flares; while the use of prednisolone (>10 mg/day) and immunosuppressive drugs at the time of conception reduced the risk of SLE flares independently. The predicting factors identified from this study were similar to many of those mentioned in the aforementioned studies. However, this study could not demonstrate that the presence of ACL/LAC was an independent factor for poor pregnancy outcomes. This might relate to the small number of patients with poor pregnancy outcome, who were among those with a positive test for these antibodies, as previously discussed. A larger study, including more patients with APL/LAC, needs to be carried out in order to verify this association in Thai patients.
The use of mSLEDAI-2K, the modified SFI and modified SLE disease activity severity score would have caused a limitation in this study. The SLE disease activity or flares would be underestimated (as the score for anti-dsDNA and complement would not be counted), making it difficult to compare this study with those that used scores from the original version. However, the mSLEDAI-2K has been shown to correlate very well (r = 0.924) with the original SLEDAI-2K.[13] In addition, use of the mSLEDAI-2K score in this study reflects real world practice, as many institutions could not perform anti-dsDNA and complements routinely. The small number of patients with positive ACL/LAC did not demonstrate the effect of these antibodies on APOs clearly. However, all of the patients in this study were taken care of by the same group of rheumatologists, who collectively made more uniformed therapeutic decisions, which should add more strength to the outcomes.
5 Conclusion
This study showed that pregnancy outcomes in Thai patients with SLE has improved over a 25-year period. However, a significant number of APOs were still observed. Renal involvement and flares during pregnancy were associated with both poor fetal and maternal outcomes. The beneficial effect of HCQ in lupus pregnancy was not demonstrated clearly, but there was a trend in favor of better pregnancy outcomes among the HCQ users. Age ≥ 25 years at conception, the presence of or ever having renal involvement during pregnancy, presence of SLE flare and hematologic involvement during pregnancy were predicting factors for poor pregnancy outcomes. Cutaneous vasculitis, and renal, hematologic and mucocutaneous involvement during pregnancy predicted SLE flare. The effect of APL/LAC on pregnancy outcomes in Thai populations needs further investigations.
Acknowledgments
The authors thank Mrs. Waraporn Sukitawut, Ms. Saowanee Pantana and Ms. Phimwalan Konkaeo for their secretarial assistance.
Author contributions
Conceptualization: Worawit Louthrenoo, Thananant Trongkamolthum, Nuntana Kasitanon, Antika Wongthanee.
Data curation: Worawit Louthrenoo, Thananant Trongkamolthum.
Formal analysis: Worawit Louthrenoo, Antika Wongthanee.
Investigation: Worawit Louthrenoo, Thananant Trongkamolthum.
Methodology: Worawit Louthrenoo, Thananant Trongkamolthum.
Supervision: Worawit Louthrenoo.
Validation: Worawit Louthrenoo, Antika Wongthanee.
Visualization: Worawit Louthrenoo, Antika Wongthanee.
Writing – original draft: Worawit Louthrenoo, Thananant Trongkamolthum.
Writing – review & editing: Worawit Louthrenoo, Thananant Trongkamolthum, Nuntana Kasitanon, Antika Wongthanee.
Abbreviations: 95% CI = 95% confidence intervals, ACL = anti-cardiolipin antibodies, ACR = American College of Rheumatology, ANA = antinuclear antibodies, Anti-dsDNA = anti-double stranded DNA antibodies, Anti-Ro = anti-Ro antibodies, Anti-Sm = anti-Smith antibodies, AOR = adjusted odds ratio, APL = anti-phospholipid antibodies, APO = adverse pregnancy outcomes, APS = anti-phospholipid syndrome, HCQ = hydroxychloroquine, HELLP syndrome = hemolysis, elevated liver enzymes, and low platelet count syndrome, IM drugs = immunosuppressive drugs, LAC = lupus coagulants, LBW = low birth weight, mSLEDAI-2K = modified Systemic Lupus Erythematosus Disease Activity Index-2000, OR = odds ratio, PGA = physician global assessment, PIH = pregnancy induced hypertension, PPH = post-partum hemorrhage, PROM = premature rupture of membrane, SDI = the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, SFI = the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE flare index, SGA = small for gestational age, SLE = systemic lupus erythematosus, VLBW = very low birth weight.
How to cite this article: Louthrenoo W, Trongkamolthum T, Kasitanon N, Wongthanee A. Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus: a STROBE-compliant study. Medicine. 2021;100:5(e24553).
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
∗ twin pregnancy.
† maternal complications (PROM + oligohydramnios = 1, PROM + post-partum hemorrhage = 1, PROM + PIH = 1, PIH + eclampsia = 1), ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, LBW = low birth weight, PIH = pregnancy induced hypertension, PPH = post-partum hemorrhage, PROM = premature rupture of membrane, SGA = small for gestational age.
∗ number of positive tests/number tested.
† excluding hydroxychloroquine, −6 M = 6 months prior to conception, ACR = American College of Rheumatology, ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, APS = anti-phospholipid syndrome, BW = birth weight, LBW = low birth weight, SDI = Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index, mSLEDAI-2K = modified systemic lupus erythematosus disease activity index – 2000, SGA = small for gestational age.
∗ number of positive tests/number tested.
† excluding hydroxychloroquine, −6 M = 6 months prior to conception, ACR = American College of Rheumatology, ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, APS = anti-phospholipid syndrome, SDI = Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index, SLEDAI-2K = systemic lupus erythematosus disease activity index – 2000.
a AOR (95% CI) = 4.15 (1.10–15.72), P = .036.
b AOR (95% CI) = 9.21 (1.03–82.51), P = .047.
c AOR (95% CI) = 3.89 (0.99–15.20), P = .051.
d AOR (95% CI) = 0.11 (0.02–0.85), P = .034.
e AOR (95% CI) = 6.0 (1.77–20.52), P = .004.
f AOR (95% CI) = 4.46 (1.44–13.78), P = .009.
g AOR (95% CI) = 10.01 (3.07–32.62), P < .001.
HCQ = hydroxychloroquine, IM drugs = immunosuppressive drugs, excluding HCQ, n = number of pregnancies with positive conditions, N1 = number of pregnancies, N2 = number of pregnancies with live births.
a AOR (95% CI) = 8.45 (1.58–45.30), P = .013.
b AOR (95% CI) = 9.24 (1.70–50.24), P = .010.
c AOR (95% CI) = 0.08 (0.01–0.68), P = .021.
d AOR (95% CI) = 33.87 (1.05–1,094.65), P = .047.
e AOR (95% CI) = 31.89 (6.66–152.69), P < .001.
f AOR (95% CI) = 9.17 (1.83–45.90), P = .007.
g AOR (95% CI) = 128.00 (4.60–3564.46), P = .004.
HCQ = hydroxychloroquine, IM drugs = immunosuppressive drugs, excluded HCQ, n = number of pregnancies with positive conditions, N1 = number of pregnancies, N2 = number of pregnancies with live birth. | MYCOPHENOLATE MOFETIL | DrugsGivenReaction | CC BY-NC | 33592909 | 19,221,827 | 2021-02-05 |
What is the weight of the patient? | Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus: A STROBE-compliant study.
Studies on predicting factors for adverse pregnancy outcomes (APOs) in Thai patients with systemic lupus erythematosus (SLE) are limited. This retrospective observation study determined APOs and their predictors in Thai patients with SLE.Medical records of pregnant SLE patients in a lupus cohort, seen from January 1993 to June 2017, were reviewed.Ninety pregnancies (1 twin pregnancy) from 77 patients were identified. The mean age at conception was 26.94 ± 4.80 years. At conception, 33 patients (36.67%) had active disease, 23 (25.56%) hypertension, 20 (22.22%) renal involvement, and 6 of 43 (13.95%) positive anti-cardiolipin antibodies or lupus anti-coagulants, and 37 (41.11%) received hydroxychloroquine. Nineteen patients (21.11%) had pregnancy loss. Of 71 successful pregnancies, 28 (31.11%) infants were full-term, 42 (46.67%) pre-term and 1 (11.11%) post-term; 19 (26.39%) were small for gestational age (SGA), and 38 (52.58%) had low birth weight (LBW). Maternal complications occurred in 21 (23.33%) pregnancies [10 (11.11%) premature rupture of membrane (PROM), 8 (8.89%) pregnancy induced hypertension (PIH), 4 (4.44%) oligohydramnios, 2 (2.22%) post-partum hemorrhage, and 1 (1.11%) eclampsia]. Patients aged ≥ 25 years at pregnancy and those ever having renal involvement had predicted pregnancy loss with adjusted odds ratio (AOR) [95% CI] of 4.15 [1.10-15.72], P = .036 and 9.21 [1.03-82.51], P = .047, respectively. Renal involvement predicted prematurity (6.02 [1.77-20.52, P = .004), SGA (4.46 [1.44-13.78], P = .009), and LBW in infants (10.01 [3.07-32.62], P < .001). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception protected against prematurity (0.11 [0.02-0.85], P = .034). Flares and hematologic involvement predicted PROM (8.45 [1.58-45.30], P = .013) and PIH (9.24 [1.70-50.24], P = .010), respectively. Cutaneous vasculitis (33.87 [1.05-1,094.65], P = .047), and renal (31.89 [6.66-152.69], P < .001), mucocutaneous (9.17 [1.83-45.90], P = .007) and hematologic involvement (128.00 [4.60-3,564.46], P = .004) during pregnancy predicted flare; while prednisolone (>10 mg/day) and immunosuppressive drug use at conception reduced that risk (0.08 [0.01-0.68, P = .021).APOs remain a problem in Thai pregnant SLE patients. Renal involvement and SLE flares were associated with the risk of APOs.
1 Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ systems, characterized by remission and relapse. The disease predominantly affects women of child bearing age. Pregnancy in SLE patients is a challenging issue in clinical practice because of its association with increasing adverse outcomes in both mother and fetus.[1,2] Pregnant women with SLE have a reportedly higher rate of spontaneous abortion, fetal loss, intra-uterine growth retardation, pre-term delivery, pregnancy induced hypertension (PIH), pre-eclampsia and flares. Furthermore, pregnancy in SLE patients can cause disease exacerbation or flare, which often requires increasing doses of corticosteroids and/or immunosuppressive drugs that can have adverse effects on mother and fetus.[3,4] Thus, it is suggested that pregnancy in SLE patients should be avoided if the patients have had active severe disease within the previous 6 months, or significant heart, lung, renal and central nervous system involvement.[3,4]
With progress made in understanding the clinical course of SLE, standard instruments that determine disease activity and flares have been developed, as well as progression in medical treatment that results in improved obstetrics care of pregnant SLE patients.[3,5] Pregnancy outcomes in SLE patients have been reported widely, however, data on pregnancy outcomes from Asian countries are very limited.[6–11]
The purpose of this study was to determine pregnancy outcomes and identify independent predicting factors for adverse pregnancy outcomes (APOs) from a lupus cohort of Thai pregnant patients with SLE.
2 Patients and methods
2.1 Patients and data source
The medical records of SLE patients in a lupus cohort seen between January 1993 and June 2017 at the Division of Rheumatology, Faculty of Medicine, Chiang Mai University, Thailand were reviewed. SLE was diagnosed according to the 1997 updating the American College of Rheumatology (ACR) revised criteria for the classification of SLE.[12] Pregnant SLE patients were identified. Clinical manifestations, laboratory investigations, treatment, and SLE disease activity were recorded from 6 months prior to conception (−6 M) until 6 weeks after termination of pregnancy or delivery or the post-partum period. Pregnancy data were recorded at the time of conception or when the pregnancy was documented. The data were captured at −6 M, 3 months prior to conception (−3 M), at the time of conception, 1st trimester, 2nd trimester, 3rd trimester, and the post-partum period. If the patients had more than 1 visit during each period, the mean SLE disease activity of each period was used for statistical analysis. Laboratory investigations, including complete blood counts, urine analysis, and renal and liver functions were recorded routinely. The 24-hour urine protein creatinine ratio (24hour UPCI) [urine protein in gm/day to urine creatinine in gm/day] was determined only in cases with lupus nephritis (urine protein >0.5 gm/day). SLE patients were followed up usually in the clinic at 1 to 3 month intervals, depending on SLE disease activity or other clinical encounters. If the patients had more than 1 pregnancy, each one was considered as a separate observation and counted as an individual case.
Patients in the clinic should have been in clinical remission or have stable low disease activity (prednisolone ≤10 mg/day without immunosuppressive drugs other than anti-malarial medication) for a minimum of 12 months to allow for pregnancy to occur. Those who developed mild to moderate flares during pregnancy were administered prednisolone at a dosage of up to 0.50 mg/kg/day, and those with severe flares received >0.50 to 1.00 mg/kg/day. Anti-malarial medication was given according to clinical indications, e.g., skin rashes, oral ulcers or alopecia. Immunosuppressive drugs, particularly azathioprine and cyclosporine, were given to cases of severe flares. Cases in which the patients received methotrexate, cyclophosphamide or mycophenolate mofetil at the time of pregnancy, had these immunosuppressive drugs discontinued immediately and replaced with azathioprine or cyclosporine.
2.2 SLE disease activity and flare assessment
The modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K)[13] was used in this study to determine SLE disease activity (as anti-dsDNA and complements were not routinely available at this institution). The severity of SLE disease activity was classified according to that of Abrahamowicz et al,[14] but the mSLEDAI-2K instrument was used instead of the original SLEDAI-2K; remission [mSLEDAI-2K = 0], mild disease activity [mSLEDAI-2K = 1–5], moderate disease activity [mSLEDAI-2K = 6–10], high disease activity [mSLEDAI-2K = 11–19] and very high disease activity [mSLEDAI-2K = ≥20]). The severity of SLE flare (mild or moderate flare and severe flare) followed the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE flare index (SFI).[15] As the physician global assessment (PGA) was not recorded routinely, the SFI was modified by excluding the PGA items (mSFI). Organ damage accrual was determined using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).[16]
2.3 Pregnancy outcomes
The definition of maternal complications (premature rupture of membrane [PROM], oligohydramnios, pregnancy induced hypertension [PIH], pre-eclampsia, eclampsia, and direct and indirect maternal death), and fetal outcomes (pregnancy loss, miscarriage or spontaneous abortion, intra-uterine fetal death, medical termination of pregnancy, pre-term delivery, term delivery, post-term delivery, neonatal death, small for gestational age [SGA], and infant birth weight) followed that of standard references.[17]
2.4 Ethical statement
This study was performed in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This study was approved by the Ethic Committee of the Faculty of Medicine, Chiang Mai University (no. 215/2017).
2.5 Statistical analysis
STATA 14.2 computer software (Stata Corporation, Texas USA) was used for data processing and statistical analysis. As some patients had more than 1 pregnancy, each one was considered individually for statistical analysis. Continuous variables were presented as mean ± standard deviation (SD) or median (min-max), with categorical variables presented as percent. The Student t test and Wilcoxon rank sum test were used to determine the differences between 2 independent samples of continuous variables. One-way analysis of variance (ANOVA) and the Kruskal–Wallis test were used for more than 2 samples, with normal and non-normal distribution, respectively. The Chi-Squared test or Fisher exact test was used to determine associations among the categorical variables, where appropriate. Firth's logistic regression was used to predict the odds ratio (OR) and 95% confidence intervals (95% CI) when the outcome contained cell counts of zero. Variables with a P value <.20 from univariate analysis were entered into multiple logistic regression analysis, and reported as adjusted odds ratio (AOR) and 95% CI. A P ≤ .05 was considered as being a statistically significant difference.
3 Results
3.1 Demographics and characteristics of pregnant SLE patients
From a cohort of 1167 female SLE patients, 90 pregnancies occurred from 77 patients (1, 2, and 3 pregnancies in 66, 9 and 2 patients, respectively). Their mean age at SLE onset and age at pregnancy was 21.63 ± 5.89 years and 26.94 ± 4.80 years, respectively. Pregnancies occurred at the time of SLE diagnosis, and < 5 years and ≥ 5 years after SLE diagnosis in 7 (7.78%), 49 (54.44%) and 34 (37.78%) pregnancies, respectively. Of the 90 pregnancies, 45 (50.00%), 25 (27.78%), and 20 (22.22%) were the first, second and third or more, respectively. Their mean cumulative ACR classification criteria and SDI score were 5.49 ± 1.15 and 0.40 ± 0.72, respectively. The mean ± SD mSLEDAI-2K score at −6 M and time of conception was 1.72 ± 3.22 and 1.90 ± 3.44, respectively. Active disease at the time of conception (mSLEDAI-2K score ≥ 0) was observed in 33 of 90 pregnancies (36.67%), and all of them were unplanned. Active organ involvement at the time of conception was renal (urine protein creatinine ratio >0.5) in 20 (22.22%) pregnancies, mucocutaneous lesions in 15 (16.67%), cutaneous vasculitis in 2 (2.22%), and arthritis and hematologic abnormalities in 1 (1.11%) of each.
Co-morbidities were seen as follows: hypertension in 23 (25.56%) pregnancies, dyslipidemia in 8 (8.89%), thalassemia in 7 (7.78%), anti-phospholipid syndrome in 3 (3.33%), diabetes mellitus in 1 (1.11%), and others in 19 (21.11%) [hepatitis C virus infection, avascular necrosis of the hip, stroke and atrial secundum defect, and past history of cryptococcal meningitis, pneumocystis jirovecii pneumonia, and past treatment of pulmonary tuberculosis]. None of the patients drank alcohol or smoked.
Antinuclear antibodies (ANA) were observed in 89 pregnancies (98.89%). Anti-double stranded DNA (anti-dsDNA), anti-Smith (anti-Sm), anti-cardiolipin (ACL), lupus coagulants (LAC), and anti-Ro (anti-Ro) antibodies were observed in 50 of 85 (58.82%), 1 of 12 (8.33%), 4 of 58 (6.89%), 3 of 42 (7.14%), and 21 of 46 (45.65%) pregnancies that had been tested, respectively.
Patients in 15 of the 90 pregnancies (16.67%) had not received any specific SLE medication at the time of conception. Patients in 57 (63.33%) of the pregnancies received prednisolone at a dose of ≤10 mg/day, and in 16 (17.78%) at ≥ 10 mg/day, with the mean dosage of 10.77 ± 11.73 mg/day. Patients also received hydroxychloroquine (HCQ) in 37 (41.11%) pregnancies, cyclophosphamide in 6 (6.67%), mycophenolate mofetil in 4 (4.40%), azathioprine in 10 (11.11%), and cyclosporine in 3 (3.33%). Both cyclophosphamide and mycophenolate mofetil were switched to azathioprine or cyclosporine when the pregnancy was documented.
3.2 Overall pregnancy outcomes
Of the 90 pregnancies, 19 (21.11%) were lost (spontaneous abortion in 12 (13.33%) [7 in the 1st trimester and 5 in the 2nd], medical termination in 5 (5.56%) [1 in the 1st trimester and 4 in the 2nd], and dead fetus in the utero (1 in each 2nd and 3rd trimester). Of the 71 (78.89%) successful pregnancies, 28 (31.11%) were full-term, 42 (46.67%) pre-term (1 twin pregnancy), and 1 (1.11%) was a post-term delivery, resulting in 72 live born infants. Mode of delivery among the live births were vaginal in 52 (73.24%) and cesarean section in 19 (26.76%). The mean ± SD duration of pregnancy with live born infants was 35.76 ± 3.58 weeks. The mean ± SD weight of the 72 live born infants was 2,367.33 ± 640.30 gm (range 720–3853 gm), with normal birth weight (≥2500 gm), low birth weight (LBW) [1500–2499 gm], and very low birth weight (VLBW) [<1500 gm] in 34 (47.22%), 30 (41.67%) and 8 (11.11%) infants, respectively. SGA infants occurred in 19 live born infants (26.39%). There was 1 neonatal death (1.11%). No infants had congenital anomalies or completed heart block.
Maternal complications occurred in 21 (23.33%) pregnancies. PROM occurred in 10 (11.11%) pregnancies, PIH in 8 (8.89%), oligohydramnios in 4 (4.44%), post-partum hemorrhage in 2 (2.22%), and eclampsia in 1 (1.11%). One concomitant PROM and oligohydramnios, PROM and post-partum hemorrhage, PROM and PIH, and PIH and eclampsia occurred in each pregnancy. There were no cases of anti-partum hemorrhage, post-partum endometritis, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), pre-eclampsia or maternal death. Thirty seven flares (41.11%) were mild to moderate and severe in 9 (24.32%) and 28 (75.68%) pregnancies, respectively.
3.3 Effect of renal involvement, hypertension, presence of anti-cardiolipin antibodies and/or lupus anti-coagulants and SLE flares on pregnancy outcomes
The effects of renal involvement, hypertension, and the presence of ACL/LAC and SLE flares on pregnancy outcomes were determined and are shown in Table 1.
Table 1 Effect of active renal involvement during pregnancy, hypertension at the time of conception, presence of anti-phospholipid antibodies and SLE flares during pregnancy on pregnancy outcomes.
Renal involvement Hypertension ACL/LAC Flares
Yes No P value Yes No P value Yes No P value Yes No P value
Successful pregnancy, n (%) 30 (75.00) 41 (82.00) .419 16 (69.57) 55 (82.09) .204 4 (66.67) 32 (86.49) .248 32 (86.49) 39 (73.58) .140
Pregnancy duration, in weeks, mean ± SD 34.34 ± 4.50 36.80 ± 2.26 .009 35.60 ± 2.47 35.81 ± 3.86 .838 38.50 ± 2.52 36.20 ± 3.45 .209 34.43 ± 3.91 36.85 ± 2.90 .004
Fetal weight, in grams, mean ± SD 2,029.52 ± 611.82 2,622.76 ± 540.06 <.001 2,147.65 ± 580.34 2,435.24 ± 647.59 .106 2,680.00 ± 557.32 2,379.94 ± 749.66 .447 2097.58 ± 615.13 2595.59 ± 575.07 .001
Fetal outcomes
Live birth, n (%) 31 (75.61)∗ 41 (82.00) .456 17 (70.83)∗ 55 (82.09) .244 4 (66.67) 32 (86.49) .248 33 (86.84)∗ 39 (73.58) .125
Term, n (%) 6 (15.00) 22 (44.00) .003 7 (30.43) 21 (31.34) .935 3 (50.00) 14 (37.84) .666 9 (24.32) 19 (35.85) .245
Pre-term, n (%) 24 (58.54)∗ 19 (38.00) .051 10 (41.67)∗ 33 (49.25) .523 1 (16.67) 17 (45.95) .177 24 (63.16)∗ 19 (35.85) .010
Post-term, n (%) 1 (2.50) 0 .444 0 1 (1.49) >.999 0 1 (2.70) >.999 0 1 (1.89) >.999
Total fetal loss, n (%) 10 (25.00) 9 (18.00) .419 7 (30.43) 12 (17.91) .204 2 (33.33) 5 (13.51) .248 5 (13.51) 14 (26.42) .140
Spontaneous abortion, n (%) 6 (15.00) 6 (12.00) .677 4 (17.39) 8 (11.94) .507 1 (16.67) 4 (10.81) .547 3 (8.11) 9 (16.98) .223
Medical termination, n (%) 2 (5.00) 3 (6.00) >.999 2 (8.70) 3 (4.48) .599 1 (16.67) 1 (2.70) .262 1 (2.70) 4 (7.55) .645
Dead fetus in the utero, n (%) 2 (5.00) 0 .195 1 (4.35) 1 (1.49) .448 0 0 1 (2.70) 1 (1.89) >.999
Neonatal death, n (%) 1 (2.50) 0 .444 1 (4.35) 0 .256 0 1 (2.70) >.999 1 (2.70) 0 .411
SGA, n (%) 13 (32.50) 6 (12.00) .018 7 (30.43) 12 (17.91) .204 1 (16.67) 12 (32.43) .649 11 (29.73) 8 (15.09) .094
LBW (< 2500 grams), n (%) 25 (60.98)∗ 13 (26.00) .001 11 (45.83)∗ 27 (40.30) .637 1 (16.67) 18 (48.65) .143 23 (60.53)∗ 15 (28.30) .002
Maternal complications†, n (%) 30 (75.00) 15 (30.00) <.001 16 (69.57) 29 (43.28) .030 2 (33.33) 18 (48.65) .669 37 (100.00) 8 (15.09) <.001
PROM, n (%) 6 (15.00) 4 (8.00) .294 1 (4.35) 9 (13.43) .232 0 4 (10.81) >.999 8 (21.62) 2 (3.77) .008
Oligohydramnios, n (%) 3 (7.50) 1 (2.00) .319 1 (4.35) 3 (4.48) >.999 0 2 (5.41) >.999 2 (5.41) 2 (3.77) >.999
PPH, n (%) 0 2 (4.00) .501 0 2 (2.99) >.999 0 1 (2.70) >.999 0 2 (3.77) .510
PIH, n (%) 5 (12.50) 3 (6.00) .282 1 (4.35) 7 (10.45) .375 0 3 (8.11) >.999 5 (13.51) 3 (5.66) .198
Eclampsia, n (%) 0 1 (2.00) >.999 0 1 (1.49) >.999 0 1 (2.70) >.999 0 1 (1.89) >.999
Flares, n (%) 27 (67.50) 10 (20.00) <.001 14 (60.87) 23 (34.33) .026 2 (33.33) 14 (37.84) >.999
Forty pregnancies were shown to have active nephritis during pregnancy. Active renal involvement occurred in 30, 30, and 26 pregnancies during the 1st, 2nd, and 3rd trimester, respectively, which was significantly higher than the 20 pregnancies seen at the time of conception (P < .001). When compared to patients without renal involvement during pregnancy, those with it had significantly shorter mean pregnancy duration (34.34 ± 4.40 weeks vs 36.80 ± 2.26 weeks, P = .003), lower fetal birth weight among live births (2029.52 ± 611.82 gm vs 2622.76 ± 540.06 gm, P < .001), and a higher proportion of LBW infants (60.98% vs 26.00%, P < .001), and SGA infants (32.50% vs 12.00%, P = .018). Although the proportion among live birth infants was not different, those with renal involvement had a significantly lower proportion of full-term infants (15.00% vs 44.00%, P = .003) and almost significantly higher proportion of pre-term infants (58.54% vs 38.00%, P = .051). There was no statistically significant difference in fetal loss among the 2 groups. The maternal complications in those with renal involvement during pregnancy were significantly higher (75.00% vs 30.00%, P < .001), which was due to a higher proportion of patients with SLE flare (67.50% vs 20.00%, P < .001). Other maternal complications, including PROM, oligohydramnios and PIH, also were higher proportionally, but they did not reach statistical significance.
Overall, there were no statistically significant differences in adverse fetal outcomes among patients with or without hypertension during pregnancy. However, pregnancy outcomes among patients with hypertension tended to have a lower proportion of live birth infants, and higher proportion of fetal loss (both spontaneous and medical terminations), SGA and LBW among full-term infants, and a lower mean fetal birth weight. Maternal complications were significantly higher in patients with hypertension (69.57% vs 43.28%, P = .030), which was due mainly to the higher proportion of those with SLE flares (60.48% vs 34.33%, P = .026). It was interesting that the proportion of PROM and PIH was lower in patients with hypertension, but with no significance.
The effect of anti-cardiolipin antibodies (ACL) and lupus anticoagulant (LAC) tests on pregnancy outcomes also was determined. Unfortunately, these 2 tests were determined in only approximately 50% of the patients. ACA and LAC were positive in a small proportion of the patients (4 of 58 or 6.89% and 3 of 42 or 7.14% of those tested, respectively). Overall, there was no statistically significant difference between either the fetal and maternal outcomes among pregnant patients with positive ACL/LAC or those without; however, those with positive ACL/LAC tended to have a lower proportion of live births and full-term birth infants, and higher proportion of fetal losses. It was interesting that the proportion of SGA, LBW, and maternal complication in the ACL/LAC positive patients also was lower, but without statistical significance. This might be due to the small number of patients in this group.
The effect of flares on pregnancy outcomes also was determined. When compared to SLE patients without flares during pregnancy, those with them had significantly shorter duration of pregnancy (34.43 ± 3.91 weeks vs 36.85 ± 2.90 weeks, P = .004), and lower mean fetal weight among live births (2097.58 ± 615.13 gm vs 2595.59 ± 575.07 gm, P = .001). Although the proportion of live birth infants and fetal loss was no different between the 2 groups, the patients with flares had a significantly higher proportion of pre-term births and LBW infants (63.16% vs 35.85%, P = .010, and 60.53% vs 28.30%, P = .002, respectively). The proportion of SGA infants also was higher, but did not reach statistical significance (29.73% vs 15.09%, P = .094). The adverse maternal outcomes were higher (100.00% vs 15.09%, P < .001), particularly of PROM (21.62% vs 3.77%, P < .008).
3.4 Effect of HCQ used on pregnancy outcomes
The effect of HCQ used during pregnancy on pregnancy outcomes was determined. Overall, there was no statistically significant difference in fetal outcomes among patients who did or did not receive HCQ during pregnancy. However, infants born to mothers who used HCQ tended to have a higher proportion of full term births (37.84% vs 26.42%, P = .249), and lower proportion of SGA (16.22% vs. 24.53%, P = .342) and LBW (36.84% vs 45.28%, P = .421). The proportion of live birth infants and fetal loss was similar between the 2 groups (78.95% vs 79.25%, P = .972, and 21.62% vs. 20.75%, P = .921, respectively). The proportion of maternal complications was lower among patients who received HCQ, and it almost reached statistical significance (37.84% vs 58.49%, P = .054). The proportion of maternal PROM, PIH and flares in the HCQ group also was lower, but did not reach statistical significance (5.41% vs 15.09%, P = .150; 5.41% vs 11.32%, P = .332, and 32.43% vs 47.17%, P = .162, respectively).
3.5 Pregnancy outcomes according to period of pregnancy, and between the first and subsequence pregnancy
The pregnancy outcomes according to the period of pregnancy (1993–2001, 2002–2009, and 2010–2017) were determined. Overall, there was no statistically significant difference in fetal or maternal outcomes between each pregnancy period. However, when comparing the pregnancy outcomes between 2010–2017, 2002–2009, and 1993–2001, fetal outcomes among pregnancies during 2010–2017 tended to have a higher proportion of live births (80.85% vs 76.00% vs 78.95%, P = .890), full-term birth infants (36.17% vs 32.00% vs 16.67%, P = .313), but with a lower proportion of pre-term birth infants (42.55% vs 44.00% vs 63.16%, P = .294), and pregnancy loss (19.15% vs 24.00% vs 22.22%, P = .884). They also had had a higher proportion of SGA and LBW (29.79% vs 16.00% vs 5.56%, P = .070, and 48.94% vs 36.00% vs 31.58%, P = .342, respectively). The proportion of maternal complications was similar (48.94% vs 48.00% vs 55.56%, P = .868); but with a tendency for decreased proportion of PROM (8.51% vs 12.00% vs 16.67%, P = .495), PIH (8.51% vs 4.00% vs 16.67%, P = .382) and SLE flares (38.30% vs 44.00% vs 44.44%, P = .851).
The pregnancy outcomes between patients with a first pregnancy and subsequent pregnancies also were compared. Similarly, there was no significant difference in fetal and maternal outcomes between the 2 groups. However, fetal outcomes in subsequent pregnancy groups tended to have a lower proportion of live births (73.91% vs 84.44%, P = .217), full-term births (24.44% vs 37.78%, P = .172), SGA (17.78% vs 24.44%, P = .438) and LBW infants (36.96% vs 46.67%, P = .348), but higher proportion of fetal loss (26.67% vs 15.56%, P = .197). Maternal complications tended to be lower (46.67% vs 53.33%, P = .527), which was due mainly to decreased proportion of SLE flares (37.78% vs 44.44%, P = .520). The rate of caesarean section was significantly higher among subsequent pregnancies (39.39% vs 15.79%, P = .025).
3.6 Predicting factors for adverse pregnancy outcomes
In order to determine independent predicting factors for APOs, the clinical characteristics that associated with adverse fetal outcomes (pregnancy loss, prematurity, SGA and LBW), and adverse maternal outcomes (PROM, PIH and flare) were compared and are shown in Tables 2 and 3, respectively.
Table 2 Comparison of clinical characteristics of adverse fetal outcomes in pregnant SLE patients.
Successful pregnancy Pregnancy loss Pre-maturity Full term + post term SGA Non-SGA LBW Normal BW
Characteristics (n = 71) (n = 19) P value (n = 42) (n = 29) P value (n = 19) (n = 52) P value (n = 37) (n = 34) P value
Age at pregnancy (in years), mean ± SD 26.30 ± 4.55 29.31 ± 5.09 .014 26.46 ± 4.73 26.07 ± 4.34 .726 25.09 ± 3.85 26.74 ± 4.73 .178 26.12 ± 4.61 26.50 ± 4.54 .726
Disease duration prior to conception (in years), mean ± SD 4.92 ± 5.01 6.99 ± 5.37 .081 4.38 ± 3.96 5.71 ± 6.21 .574 5.20 ± 4.26 4.82 ± 5.29 .451 4.54 ± 4.08 5.34 ± 5.89 .954
Co-morbidities
Hypertension, n (%) 16 (22.54) 7 (36.84) .204 9 (21.43) 7 (24.14) .788 7 (36.84) 9 (17.31) .081 10 (27.03) 6 (17.65) .345
Diabetes, n (%) 1 (1.41) 0 >.999 1 (2.38) 0 >.999 1 (5.26) 0 .268 1 (2.70) 0 >.999
Dyslipidemia, n (%) 5 (7.04) 3 (15.79) .234 3 (7.14) 2 (6.90) >.999 4 (21.05) 1 (1.92) .016 4 (10.81) 1 (2.94) .359
APS, n (%) 2 (2.82) 1 (5.26) .513 0 2 (6.90) .163 0 2 (3.85) >.999 0 2 (5.88) .226
ANA positive, n (%) 70 (98.59) 19 (100.00) >.999 41 (97.62) 29 (100.00) >.999 19 (100.00) 51 (98.08) >.999 37 (100.00) 33 (97.06) .479
Anti-dsDNA, n (%)∗ 41/67 (61.19) 9/18 (50.00) .392 26/40 (65.00) 15/27 (55.56) .436 13/19 (68.42) 28/48 (58.33) .445 25/37 (67.57) 16/30 (53.33) .234
Anti-Sm, n (%)∗ 0/11 1/1 (100.00) .083 0/7 0/4 0/2 0/9 0/6 0/5
ACL/LAC, n (%)∗ 4/36 (11.11) 2/7 (28.57) .248 1/18 (5.56) 3/18 (16.67) .603 1/13 (7.69) 3/23 (13.04) >.999 1/19 (5.26) 3/17 (17.65) .326
Anti-Ro, n (%)∗ 16/38 (42.11) 5/8 (62.50) .293 7/17 (41.18) 9/21 (42.86) .917 6/13 (46.15) 10/25 (40.00) .715 11/23 (47.83) 5/15 (33.33) .376
Anti-La, n (%)∗ 16/38 (42.11) 4/9 (44.44) .898 7/17 (41.18) 9/21 (42.86) .917 6/13 (46.15) 10/25 (40.00) .715 11/23 (47.83) 5/15 (33.33) .376
Pregnancy loss (ever), n (%) 23 (32.39) 9 (47.37) .226 12 (28.57) 11 (37.93) .407 6 (31.58) 17 (32.69) .929 11 (29.73) 12 (35.29) .617
Cumulative number of ACR criteria, mean ± SD 5.46 ± 1.11 5.58 ± 1.35 .704 5.38 ± 1.17 5.59 ± 1.02 .446 5.42 ± 1.02 5.48 ± 1.15 .842 5.35 ± 1.06 5.59 ± 1.16 .371
Disease activity (mSLEDAI-2K) at −6M, mean ± SD 1.34 ± 2.43 3.16 ± 5.05 .325 1.36 ± 2.44 1.31 ± 2.46 .960 1.42 ± 2.48 1.31 ± 2.44 .874 1.38 ± 2.53 1.29 ± 2.36 .933
Disease activity (mSLEDAI-2K) at conception, mean ± SD 1.58 ± 2.74 3.16 ± 5.22 .562 1.81 ± 2.98 1.24 ± 2.36 .385 2.16 ± 2.99 1.36 ± 2.64 .222 1.92 ± 3.22 1.20 ± 2.08 .566
Remission, n (%) 45 (63.38) 12 (63.16) .321 25 (59.52) 20 (68.97) .629 10 (52.63) 35 (67.31) .444 23 (62.16) 22 (64.71) .955
Mild, n (%) 19 (26.76) 3 (15.79) 13 (30.95) 6 (20.69) 6 (31.58) 13 (25.00) 10 (27.03) 9 (26.47)
Moderate and high, n (%) 7 (9.86) 4 (21.05) 4 (9.52) 3 (10.34) 3 (15.79) 4 (7.69) 4 (10.81) 3 (8.82)
SDI score at conception, mean ± SD 0.35 ± 0.66 0.58 ± 0.90 .400 0.36 ± 0.62 0.34 ± 0.72 .612 0.21 ± 0.42 0.40 ± 0.72 .463 0.24 ± 0.55 0.47 ± 0.75 .169
Active organ involvement during pregnancy
Renal 30 (42.25) 10 (52.63) .419 23 (54.76) 7 (24.14) .010 13 (68.42) 17 (32.69) .007 24 (64.86) 6 (17.65) <.001
Mucocutaneous 23 (32.39) 4 (21.05) .338 12 (28.57) 11 (37.93) .407 4 (21.05) 19 (36.54) .217 9 (24.32) 14 (41.18) .130
Vasculitis 2 (2.82) 1 (5.26) .513 1 (2.38) 1 (3.45) >.999 1 (5.26) 1 (1.92) .466 1 (2.70) 1 (2.94) >.999
Arthritis 2 (2.82) 0 >.999 2 (4.76) 0 .510 0 2 (3.85) >.999 1 (2.70) 1 (2.94) >.999
Hematologic 8 (11.27) 0 .125 6 (14.29) 2 (6.90) .333 4 (21.05) 4 (7.69) .197 5 (13.51) 3 (8.82) .532
Medication at conception
Prednisolone, n (%) 56 (78.87) 17 (89.47) .294 32 (76.19) 24 (82.76) .505 15 (78.95) 41 (78.85) .993 31 (83.78) 25 (73.53) .290
Dose (in mg/day), mean ± SD 9.11 ± 9.38 16.25 ± 16.58 .058 9.53 ± 9.56 8.54 ± 9.32 .412 12.50 ± 12.32 7.86 ± 7.88 .162 9.11 ± 9.39 9.10 ± 9.57 .823
Prednisolone >10 mg/day 10 (14.08) 6 (31.58) .076 6 (14.29) 4 (13.79) .953 5 (26.32) 5 (9.62) .073 6 (16.22) 4 (11.76) .590
Hydroxychloroquine, n (%) 29 (40.85) 8 (42.11) .921 15 (35.71) 14 (48.28) .290 6 (31.58) 23 (44.23) .337 13 (35.14) 16 (47.06) .307
Dose (in mg/day), mean ± SD 191.38 ± 86.67 256.25 ± 129.39 .144 183.33 ± 79.43 200.00 ± 96.08 .762 166.67 ± 51.64 197.83 ± 93.52 .533 165.38 ± 55.47 212.50 ± 102.47 .275
Immunosuppressive drug† 18 (25.35) 4 (21.05) .699 10 (23.81) 8 (27.59) .719 5 (26.32) 13 (25.00) .910 12 (32.43) 6 (17.65) .153
Mycophenolate mofetil, n (%) 4 (5.63) 0 .575 2 (4.76) 2 (6.90) >.999 1 (5.26) 3 (5.77) >.999 3 (8.11) 1 (2.94) .615
Cyclophosphamide, n (%) 3 (4.23) 3 (15.79) .106 3 (7.14) 0 .265 1 (5.26) 2 (3.85) >.999 3 (8.11) 0 .241
Azathioprine, n (%) 10 (14.08) 0 .083 5 (11.90) 5 (17.24) .525 3 (15.79) 7 (13.46) .803 6 (16.22) 4 (11.76) .590
Cyclosporine, n (%) 2 (2.82) 1 (5.26) .513 0 2 (6.90) .163 0 2 (3.85) >.999 1 (2.70) 1 (2.94) >.999
Flare during pregnancy 32 (45.07) 5 (26.32) .140 23 (54.76) 9 (31.03) .048 11 (57.89) 21 (40.38) .189 22 (59.46) 10 (29.41) .011
Table 3 Comparison of clinical characteristics of adverse maternal outcomes in pregnant SLE patients.
Premature rupture of membrane Pregnancy induced hypertension Flares
Characteristics Yes (n = 10) No (n = 80) P value Yes (n = 8) No (n = 82) P value Yes (n = 37) No (n = 53) P value
Age at pregnancy (in years), mean ± SD 28.85 ± 4.38 26.70 ± 4.82 .182 25.92 ± 3.65 27.03 ± 4.90 .535 26.89 ± 4.75 26.97 ± 4.88 .937
Disease duration prior to conception (in years), mean ± SD 3.81 ± 3.06 5.55 ± 5.31 .521 4.67 ± 6.25 5.43 ± 5.04 .257 5.67 ± 5.45 5.14 ± 4.92 .608
Co-morbidities
Hypertension, n (%) 1 (10.00) 22 (27.50) .232 1 (12.50) 22 (26.83) .375 14 (37.84) 9 (16.98) .026
Diabetes, n (%) 0 1 (1.25) >.999 0 1 (1.22) >.999 0 1 (1.89) >.999
Dyslipidemia, n (%) 0 8 (10.00) .295 0 8 (9.76) .355 3 (8.11) 5 (9.43) .828
APS, n (%) 0 3 (3.75) >.999 0 3 (3.66) >.999 2 (5.41) 1 (1.89) .566
ANA positive, n (%) 10 (100.00) 79 (98.75) >.999 7 (87.50) 82 (100.00) .089 37 (100.00) 52 (98.11) >.999
Anti-dsDNA, n (%)∗ 5/9 (55.56) 45/76 (59.21) .833 5/7 (71.43) 45/78 (57.69) .479 20/35 (57.14) 30/50 (60.00) .792
Anti-Sm, n (%)∗ 0/1 1/11 (9.09) >.999 0/1 1/11 (9.09) >.999 0/4 1/8 (12.50) >.999
ACL/LAC, n (%)∗ 0/4 6/39 (15.38) >.999 0/3 6/40 (15.00) >.999 2/16 (12.50) 4/27 (14.81) >.999
Anti-Ro, n (%)∗ 1/4 (25.00) 20/42 (47.62) .614 2/4 (50.00) 19/42 (45.24) >.999 6/15 (40.00) 15/31 (48.39) .592
Anti-La, n (%)∗ 1/4 (25.00) 19/43 (44.19) .626 2/4 (50.00) 18/43 (41.86) >.999 6/15 (40.00) 14/32 (43.75) .808
Pregnancy loss (ever), n (%) 3 (30.00) 29 (36.25) .697 2 (25.00) 30 (36.59) .513 9 (24.32) 23 (43.40) .063
Cumulative number of ACR criteria, mean ± SD 5.30 ± 1.06 5.51 ± 1.17 0.586 5.62 ± 0.52 5.48 ± 1.20 .518 5.54 ± 1.14 5.45 ± 1.17 .725
Disease activity (mSLEDAI-2K) at -6M, mean ± SD 0.40 ± 1.26 1.89 ± 3.35 .116 0.25 ± 0.71 1.86 ± 3.33 .163 1.70 ± 3.44 1.74 ± 3.09 .696
Disease activity (mSLEDAI-2K) at conception, mean ± SD 0.70 ± 1.34 2.06 ± 3.59 .400 1.00 ± 2.14 2.00 ± 3.54 .454 2.16 ± 3.92 1.74 ± 3.09 .624
Remission, n (%) 7 (70.00) 50 (62.50) 0.450 6 (75.00) 51 (62.20) .704 22 (59.46) 35 (66.04) 0.816
Mild, n (%) 3 (30.00) 19 (23.75) 1 (12.50) 21 (25.61) 10 (27.03) 12 (22.64)
Moderate and high, n (%) 0 11 (13.75) 1 (12.50) 10 (12.20) 5 (13.51) 6 (11.32)
SDI score at conception, mean ± SD 0.50 ± 0.85 0.39 ± 0.70 .728 0 ± 0 0.44 ± 0.74 .079 0.54 ± 0.80 0.30 ± 0.64 .120
Active organ involvement during pregnancy
Renal 6 (60.00) 34 (42.50) .294 5 (62.50) 35 (42.68) .282 27 (72.97) 13 (24.53) <.001
Mucocutaneous 4 (40.00) 23 (28.75) .464 4 (50.00) 23 (28.05) .234 17 (45.95) 10 (18.87) .006
Vasculitis 0 3 (3.75) >.999 0 3 (3.66) >.999 3 (8.11) 0 .066
Arthritis 0 2 (2.50) >.999 0 2 (2.44) >.999 1 (2.70) 1 (1.89) >.999
Hematologic 2 (20.00) 6 (7.50) .190 3 (37.50) 5 (6.10) .003 8 (21.62) 0 <.001
Medication at conception
Prednisolone, n (%) 8 (80.00) 65 (81.25) .924 4 (50.00) 69 (84.15) .039 29 (78.38) 44 (83.02) .580
Dose (in mg/day), mean ± SD 5.94 ± 2.65 11.36 ± 12.78 .423 19.38 ± 27.26 10.27 ± 10.41 .755 8.88 ± 7.89 12.02 ± 13.63 .958
Prednisolone >10 mg/day 0 16 (20.00) .119 1 (12.50) 15 (18.29) .683 5 (13.51) 11 (20.75) .377
Hydroxychloroquine, n (%) 2 (20.00) 35 (43.75) .150 2 (25.00) 35 (42.68) .332 12 (32.43) 25 (47.17) .162
Dose (in mg/day), mean ± SD 125.00 ± 106.07 210.00 ± 98.37 .223 150.00 ± 70.71 208.57 ± 100.36 .382 208.33 ± 129.39 204.00 ± 84.06 .797
Immunosuppressive drug† 2 (20.00) 20 (25.00) .729 0 22 (26.83) .092 7 (18.92) 15 (28.30) .308
Mycophenolate mofetil, n (%) 1 (10.00) 3 (3.75) .381 0 4 (4.88) >.999 2 (5.41) 2 (3.77) >.999
Cyclophosphamide, n (%) 0 6 (7.50) .370 0 6 (7.32) .428 1 (2.70) 5 (9.43) .208
Azathioprine, n (%) 1 (10.00) 9 (11.25) .906 0 10 (12.20) .295 4 (10.81) 6 (11.32) .940
Cyclosporine, n (%) 0 3 (3.75) >.999 0 3 (3.66) >.999 0 3 (5.66) .266
Flare during pregnancy 8 (80.00) 29 (36.25) .008 5 (62.50) 32 (39.02) .198
Factors that might be associated with adverse fetal and maternal outcomes, and those that had a statistical difference with a P value of <.2 in the univariate analysis (Tables 2 and 3) were included in the multiple logistic regression analysis (Tables 4 and 5). Independent predicting factors that increased the risk of fetal loss included age at pregnancy of ≥25 years (AOR [95% CI]) 4.15 [1.10–15.72], P = .036), and ever having renal involvement (9.21 [1.03–82.51], P = .047). Prednisolone used (>10 mg/day) at conception almost reached a predicting factor for fetal loss (3.89 [0.99–15.20], P = .051). Renal involvement during pregnancy independently predicted prematurity (6.02 [1.77–20.52], P = .004), and SGA (4.46 [1.44–13.78], P = .009) and LBW infants (10.01 [3.07–32.62], P < .001). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception independently reduced the risk of prematurity (0.11 [0.02–0.85], P = .034). SLE flares and hematologic involvement during pregnancy independently predicted PROM (8.45 [1.58–45.30], P = .013) and PIH (9.24 [1.70–50.24], P = .010), respectively. Independent predicting factors for SLE flares during pregnancy included the presence of cutaneous vasculitis (AOR [95% CI]) 33.87 [1.05–1094.65], P = .047), and renal (31.89 [6.66–152.69], P < .001), mucocutaneous (9.17 [1.83–45.90], P = .007) and hematologic involvement (128.00 [4.60–3,564.46], P = .004). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception independently reduced the risk of SLE flares during pregnancy (0.08 [0.01–0.68, P = .021).
Table 4 Univariable analysis and multiple logistic regression analysis of factors associated with adverse fetal outcomes in pregnant SLE patients.
Pregnancy loss Prematurity Small for gestational age Low birth weight
Characteristics N1 n OR (95% CI) P value N2 n OR (95% CI) P value n OR (95% CI) P value n OR (95% CI) P value
Age at pregnancy
<25 years 39 4 3.64 35 21 0.93 13 0.34 19 0.84
≥25 years 51 15 (1.01–16.37) .027a 36 21 (0.32–2.67) .886 6 (0.09–1.16) .051 18 (0.30–2.37) .718
Disease duration prior to conception
<5 years 56 8 2.87 48 28 1.11 13 0.95 26 0.78
≥5 years 34 11 (0.90–9.34) .042 23 14 (0.36–3.52) .839 6 (0.25–3.28) .929 11 (0.25–2.36) .617
Hypertension
No 67 12 2.00 55 33 0.86 12 2.79 27 1.73
Yes 23 7 (0.56–6.64) .204 16 9 (0.24–3.15) .788 7 (0.71–10.44) .081 10 (0.48–6.59) .345
Previous pregnancy
0 45 7 1.97 38 21 1.42 11 0.78 21 0.76
≥1 45 12 (0.62–6.61) .196 33 21 (0.49–4.12) .474 8 (0.23–2.56) .655 16 (0.27–2.15) .568
Pregnancy loss (ever)
No 58 10 1.88 48 30 0.65 13 0.95 26 0.78
Yes 32 9 (0.58–5.92) .226 23 12 (0.21–2.03) .408 6 (0.25–3.28) .929 11 (0.25–2.36) .617
Renal disorder (ever)
No 18 1 5.67 17 6 3.67 3 1.96 5 3.49
Yes 72 18 (0.76–249.73) .071b 54 36 (1.02–13.92) .022 16 (0.45–12.00) .330 32 (0.96–14.27) .032
SLE disease activity at conception
Remission and mild 79 15 2.44 64 38 0.91 16 2.25 33 1.25
Moderate and high 11 4 (0.46–11.06) .186 7 4 (0.14–6.76) .909 3 (0.29–14.72) .311 4 (0.19–9.22) .779
Prednisolone >10 mg/day at conception
No 74 13 2.82 61 36 1.04 14 3.36 31 1.45
Yes 16 6 (0.70–10.38) .076c 10 6 (0.22–5.55) .953 5 (0.66–16.66) .073 6 (0.31–7.68) .590
IM drugs used at conception
No 68 15 0.78 53 32 0.82 14 1.07 25 2.24
Yes 22 4 (0.17–2.93) .699 18 10 (0.24–2.83) .719 5 (0.25–3.99) .910 12 (0.65–8.33) .152
Prednisolone >10 mg/day and IM drugs used at conception
No 82 17 1.27 65 40 0.31 17 1.41 34 0.91
Yes 8 2 (0.12–7.98) .778 6 2 (0.03–2.40) .179d 2 (0.12–10.86) .704 3 (0.11–7.33) .914
HCQ used during pregnancy
No 47 11 0.75 36 23 0.67 11 0.67 21 0.60
Yes 43 8 (0.23–2.33) .577 35 19 (0.23–1.93) .410 8 (0.20–2.20) .464 16 (0.21–1.70) .287
Organ involvement during Pregnancy
Cutaneous vasculitis
No 87 18 1.92 69 41 0.68 18 2.83 36 0.92
Yes 3 1 (0.03–38.45) .598 2 1 (0.01–55.50) .789 1 (0.03–226.66) .451 1 (0.01–74.11) .952
Arthritis
No 88 19 0.71 69 40 3.64 19 0.52 36 0.92
Yes 2 0 (0.03–15.47) .829 2 2 (0.17–78.70) .410 0 (0.02–11.28) .676 1 (0.01–74.11) .952
Renal
No 50 9 1.52 41 19 3.80 6 4.46 13 8.62
Yes 40 10 (0.48–4.78) .419 30 23 (1.21–12.72) .010e 13 (1.28–16.62) .007f 24 (2.54–31.31) <.001g
Mucocutaneous
No 63 15 0.56 48 30 0.65 15 0.46 28 0.46
Yes 27 4 (0.12–2.03) .338 23 12 (0.21–2.03) .408 4 (0.10–1.76) .217 9 (0.14–1.42) .130
Hematologic
No 82 19 0.19 63 36 2.25 15 3.20 32 1.61
Yes 8 0 (0.01–3.47) .264 8 6 (0.36–24.23) .333 4 (0.52–19.11) .115 5 (0.28–11.21) .532
Flares during pregnancy
No 53 14 0.44 39 19 2.69 8 2.03 15 3.52
Yes 37 5 (0.11–1.47) .140 32 23 (0.90–8.28) .048 11 (0.62–6.84) .189 22 (1.18–10.70) .011
Table 5 Univariable analysis and multiple logistic regression analysis of factors associated with adverse maternal outcomes in pregnant SLE patients.
Premature rupture of the membrane Pregnancy induced hypertension Flares
Characteristics N n OR 95% CI P value n OR 95% CI P value n OR 95% CI P value
Age at pregnancy
<25 years 39 2 Ref. 4 Ref. 18 Ref.
≥25 years 51 8 3.44 0.62–34.83 .114 4 0.74 0.13–4.31 .690 19 0.69 (0.27–1.76) .395
Disease duration prior to conception
<5 years 56 7 Ref. 6 Ref. 22 Ref.
≥5 years 34 3 0.68 0.10–3.25 .590 2 0.52 0.05–3.17 .435 15 1.22 (0.47–3.15) .652
Hypertension
No 67 9 Ref. 7 Ref. 23 Ref.
Yes 23 1 0.29 0.01–2.36 .232 1 0.39 0.01–3.35 .375 14 2.98 (1.01–8.99) .026
Previous pregnancy
0 45 4 Ref. 4 Ref. 20 Ref.
≥1 45 6 1.58 0.34–8.16 .502 4 1.00 0.17–5.76 >.999 17 0.76 (0.30–1.91) .520
Pregnancy loss (ever)
No 58 7 Ref. 6 Ref. 28 Ref.
Yes 32 3 0.75 0.12–3.63 .697 2 0.58 0.05–3.52 .514 9 0.42 (0.14–1.15) .063
Renal disorder (ever)
No 18 1 Ref. 0 Ref. 5 Ref.
Yes 72 9 2.43 0.30–112.60 .402 8 4.88 0.27–88.50 .284 32 2.08 (0.61–8.19) .199
SLE disease activity at conception
Remission and mild 79 10 Ref. 7 Ref. 32 Ref.
Moderate and high 11 0 0.29 0.02–5.26 .401 1 1.03 0.02–9.54 .980 5 1.22 (0.27–5.27) .755
Prednisolone >10 mg/day at conception
No 74 10 Ref. 7 Ref. 32 Ref.
Yes 16 0 0.19 0.01–3.34 .254 1 0.64 0.01–5.64 .682 5 0.60 (0.15–2.11) .377
IM drugs used at conception
No 68 8 Ref. 8 Ref. 30 Ref.
Yes 22 2 0.75 0.07–4.22 .729 0 0.16 0.01–2.85 .212 7 0.59 (0.18–1.79) .308
Prednisolone >10 mg/day and IM drugs used at conception
No 82 10 Ref. 8 Ref. 36 Ref.
Yes 8 0 0.41 0.02–7.57 .546 0 0.52 0.03–9.74 .659 1 0.18 (0.00–1.55) .085c
HCQ used during pregnancy
No 47 8 Ref. 5 Ref. 20 Ref.
Yes 43 2 0.24 0.02–1.31 .062 3 0.63 0.09–3.50 .542 17 0.88 (0.35–2.22) .771
Organ involvement during pregnancy
Cutaneous vasculitis
No 87 10 Ref. 8 Ref. 34 Ref.
Yes 3 0 1.05 0.05–21.88 .973 0 1.34 0.06–28.11 .852 3 10.86 (0.54–216.71) .119d
Arthritis
No 88 10 Ref. 8 Ref. 36 Ref.
Yes 2 0 1.50 0.07–33.32 .799 0 1.89 0.08–42.79 .688 1 1.44 (0.02–115.53) .796
Renal
No 50 4 Ref. 3 Ref. 10 Ref.
Yes 40 6 2.03 0.44–10.49 .294 5 2.24 0.40–15.24 .282 27 8.31 (2.90–24.34) <.001e
Mucocutaneous
No 63 6 Ref. 4 Ref. 20 Ref.
Yes 27 4 1.65 0.31–7.69 .464 4 2.56 0.43–14.84 .196 17 3.66 (1.29–10.54) .006f
Hematologic
No 82 8 Ref. 5 Ref. 29 Ref.
Yes 8 2 3.08 0.26–21.22 .190 3 9.24 1.07–64.46 .003b 8 30.83 (1.72–553.28) .020g
Flares during pregnancy
No 53 2 Ref. 3 Ref.
Yes 37 8 7.03 1.26–70.80 .008a 5 2.60 0.46–17.73 .198
4 Discussion
Despite significant improvement in medical care for pregnant SLE patients, their APOs are still a significant issue.[5,18] Fetal loss (both spontaneous abortion and intra-uterine death), pre-term birth, intra-uterine growth retardation, SGA and LBW in the fetus, and PIH, pre-eclampsia/eclampsia and flares in the mother are among the major APOs of concern. Reports on SLE patients with APOs varied greatly among studies. This could be explain partly by the difference in time period of the study and ethnicity and socioeconomic status of the patients, as well as SLE disease activity prior to and at the time of conception, organ involvement at conception, rate and organ of flares, and prevalence of ACL/LAC or anti-phospholipid syndrome in the population studied.[1,3,19]
Progressive improvement in pregnancy outcomes over a 25-year period was observed in this study. The proportion of successful pregnancies tended to improve with an increased proportion of full-term births and decreased proportion of pre-term infants. An increased proportion of infants with SGA and LBW had slightly decreased mean fetal birth weight; although all of these changes did not reach statistical significance. The improvement in pregnancy outcomes in Thai SLE patients was similar overtime to that in many previous reports.[5,18,20,21] However, the reason for the increased frequency of SGA and LBW was not clear, despite more frequent full-term birth infants.
This study also found that pregnancy outcomes of subsequent pregnancies in SLE patients showed a slightly decreased proportion of live births, full-term births, and SGA and LBW infants, but with slightly increased proportion of fetal loss, particularly among medical terminations. The lower proportion of SGA and LBW in the subsequent pregnancies in this study was similar to that of Wallanius et al,[22] but different from that of Korese et al,[23] who found that the fetal and maternal outcomes were almost similar between the first and subsequent pregnancies, except for the latter having slightly lower pre-term births. Reasons for the higher proportion of medical terminations in subsequent pregnancies in this study were not clear, but this might have been due to decisions made by the mothers and physicians, who were afraid of severe maternal or fetal complications if the pregnancy continued, and the patients probably had a baby already from the previous pregnancy. The proportion of cesarean section delivery among the subsequent pregnancies in this study was significantly (approximately 2 times) higher than that in the first pregnancy, which was similar to that reported by Wallenius et al.[22] This could be explained by the perception of the patients and physicians in that they were afraid of possible uterine rupture during delivery.
The PIH and eclampsia prevalence of 8.89% and 1.11%, respectively, in this study was in line with many previous reports that showed prevalence of 0–19% and 0–20% for PIH[20,23–27] and pre-eclampsia, respectively[20,23–27]. However, when looking at details, studies with a high incidence of PIH had a rather low incidence of pre-eclampsia or vise-versa; except for that reported by Wu et al,[27] and Kroese et al.[23] The reason for the discordance among these reports was unclear. It is not easy in clinical practice to differentiate between PIH and pre-eclampsia in pregnant patients with pre-existing hypertension and renal disease, as hypertension is an important clinical feature in both conditions. For example, a patient with pre-existing hypertension and some degree of proteinuria has slightly increasing proteinuria (without blood cells or cellular casts in the urine, with decreasing complement level, or increasing anti-dsDNA), and elevated blood pressure in the late course of pregnancy. In this situation, many physicians might consider PIH, while others consider pre-eclampsia. A definite diagnosis of these 2 conditions probably can be made only upon patient follow-up of the patients whether both hypertension and proteinuria are resolved or returned to baseline level prior to the development of hypertension and increasing proteinuria during the post-partum period. There were no pre-eclampsia cases in this study. As patients with increasing hypertension and slightly increasing proteinuria without active urine sediment had their blood pressure, but not the proteinuria, returned to normal or baseline during the post-partum period. These patients were considered to have PIH and not pre-eclampsia.
Similar to the differentiation between PIH and pre-eclampsia, differentiation between pre-eclampsia and active nephritis flare is another challenging issue in clinical practice. Several reviews suggest that the presence of extra-renal manifestation, past history of lupus nephritis, presence of or increasing proteinuria at the early trimester of pregnancy, presence of new hypertension onset, presence of active urinary sediments, decreasing serum complement levels, increasing anti-dsDNA levels and normal serum uric acid, favor active nephritis. However, if the aforementioned conditions occur late in the pregnancy, and the patient does not have decreasing complement or increasing anti-dsDNA levels, differential diagnosis between active nephritis and pre-eclampsia would be more difficult.[28–30] The situation would be more complicated if the patient has underlying hypertension prior to pregnancy or slight proteinuria prior to conception. Furthermore, these 2 conditions can co-exist in the same patients.[31] Some authors have suggested performing a kidney biopsy in the latter condition,[29,32] as the management of active lupus nephritis and pre-eclampsia is different. Again, sometimes the diagnosis can be made only upon delivery of the fetus when the above conditions disappear or return to normal.[3] All of the patients who had significantly increasing proteinuria in this study also had active urine sediment, and the degree of proteinuria did not return to normal or baseline at the end of the post-partum period. All of them also showed renal response to an increasing dose of corticosteroid and immunosuppressive drugs, therefore, they were more likely to have active nephritis flare rather than pre-eclampsia.
The pathogenic mechanisms of PIH and pre-eclampsia are not clear, but have been reviewed widely, and included innate immunity,[33] bioactive factors (such as inflammatory cytokines, angiogenetic factors, growth factors, etc.),[34,35] oxidative stress,[36] placental vascular maladaptation,[37] and endothelial dysfunction.[38,39] Among these, endothelial dysfunction is the most likely underlying mechanism,[39] which causes imbalance between an endothelial-derived vasodilator (such as nitric oxide and prostacyclin) and vasoconstrictors (such as endothelin-1, thromboxane A2), leading to the promotion of vasoconstriction, hypertension, and pre-eclampsia. Placenta ischemia stimulates the release of several bioactive factors and inflammatory cytokines that target the endothelial cells that lead to generalized endothelial cell dysfunction, which in turn causes vascular remodeling, increased arterial stiffness, and hypertension. Current treatment options of pre-eclampsia are limited. Only low dose aspirin has been shown as effective and is recommended by several international obstetrics and gynecologists guidelines for use in preventing pre-eclampsia in high risk patients.[40] Unfortunately, the effect of low dose aspirin on pregnancy outcomes was not determined in this study.
The effect of HCQ use on pregnancy outcomes also has been of interest in lupus pregnancy, although many previous studies could not find a significant difference in overall SLE pregnancy outcomes between HCQ users and non-users.[41–43] However, some studies showed some beneficial effects of HCQ use during pregnancy, including lower rate of fetal loss and pre-term births,[20,44] intra-uterine growth restriction (IUGR) in the fetus,[44] longer duration of pregnancy,[42] flare prevention,[43,45] and decreased PIH.[46] Although no significant difference in APOs among HCQ users and non-users was demonstrated in this study, there tended to be fewer maternal complications among HCQ users, particularly in a lower proportion of PROM, PIH and SLE flares.
Several factors have been identified in association with APOs in pregnant patients with SLE. These have included the presence of renal involvement or active nephritis,[20,24,47–53] SLE flares during pregnancy,[7,24,50,53,54] active disease prior to or during pregnancy,[20,50,54–56] hypertension,[7,24,25,54–57] presence of anti-phospholipid antibodies (APL) and/or lupus anti-coagulants,[7,20,23,24,50,53,54,56,57] cytopenia,[41,50,52,54] and hypocomplementemia.[20,25,50,54,56,58,59] This study also confirmed that renal involvement during pregnancy was associated with poor pregnancy outcomes, in both the fetus and mother. However, the presence of hypertension only associated with maternal flares.
Although APOs have been reported in several studies, only a few identified independent predicting factors for adverse fetal and maternal outcomes. In addition, the results of these predicting factors also were inconsistent. For example, Cortes-Hernandez et al[25] found that the presence of ACL and hypertension during pregnancy were independent predicting factors for poor fetal outcomes, whereas the presence of anti-β2-glycoprotein-1, hypertension at conception and hypocomplemetemia were independent predicting factors for fetal loss. Kwok et al[24] found that hypertension was an independent predicting factor for fetal loss, nephritis for SGA, low serum albumin for IUGR and SLE flares for prematurity among infants; and nephritis was an independent predicting factor for SLE flares, and hypertension and high disease activity for pre-eclampsia among mothers. Ko et al[26] found that the presence of APL antibodies was an independent predicting factor for fetal loss and pre-term births, and active disease for pre-term births. Active SLE and SLE flares were independent predicting factors for PIH and IUGR among mothers. Buyon et al[41] found that the presence of LAC, hypertension, high disease activity, maternal flares, and thrombocytopenia were predictors of APOs. Lui et al[60] found that pre-eclampsia/eclampsia and thrombocytopenia were independent predicting factors for fetal loss and SLE flares in mothers. Pre-eclampsia/eclampsia also was an independent predicting factor for pre-term birth among infants. Borella et al[56] found that hypertension was an independent predicting factor for fetal loss, miscarriage and SGA, and anti-phospholipid syndrome (APS) for prematurity in infants; whereas LAC was an independent predicting factor for pre-eclampsia, and active disease at −6 M for PROM. Kalok et al[6] found that SLE flares and active disease were predicting factors for fetal loss and pre-term birth, and also SLE flares for SGA among infants. Active SLE was an independent predicting factor for SLE flares and lupus nephritis, while SLE flares and the presence of APL antibodies were independent predicting factors for pre-eclampsia among mothers. Wu et al[59] recently found that unplanned pregnancy, hypocomplementemia and urine protein >1.0 gm/day were independent predicting factors for fetal loss. This study found that age >25 years and ever having renal involvement were independent predicting factors for fetal loss, renal involvement during pregnancy, prematurity, SGA and LBW among infants. SLE flare during pregnancy and hematologic involvement were independent predicting factors for PROM and PIH, respectively, among mothers. It was interesting that the use of prednisolone (>10 mg/day) and immunosuppressive drugs at conception was an independent protecting factor for prematurity. The presence of cutaneous vasculitis, and renal, mucocutaneous and hematologic involvement during pregnancy was an independent predicting factor for SLE flares; while the use of prednisolone (>10 mg/day) and immunosuppressive drugs at the time of conception reduced the risk of SLE flares independently. The predicting factors identified from this study were similar to many of those mentioned in the aforementioned studies. However, this study could not demonstrate that the presence of ACL/LAC was an independent factor for poor pregnancy outcomes. This might relate to the small number of patients with poor pregnancy outcome, who were among those with a positive test for these antibodies, as previously discussed. A larger study, including more patients with APL/LAC, needs to be carried out in order to verify this association in Thai patients.
The use of mSLEDAI-2K, the modified SFI and modified SLE disease activity severity score would have caused a limitation in this study. The SLE disease activity or flares would be underestimated (as the score for anti-dsDNA and complement would not be counted), making it difficult to compare this study with those that used scores from the original version. However, the mSLEDAI-2K has been shown to correlate very well (r = 0.924) with the original SLEDAI-2K.[13] In addition, use of the mSLEDAI-2K score in this study reflects real world practice, as many institutions could not perform anti-dsDNA and complements routinely. The small number of patients with positive ACL/LAC did not demonstrate the effect of these antibodies on APOs clearly. However, all of the patients in this study were taken care of by the same group of rheumatologists, who collectively made more uniformed therapeutic decisions, which should add more strength to the outcomes.
5 Conclusion
This study showed that pregnancy outcomes in Thai patients with SLE has improved over a 25-year period. However, a significant number of APOs were still observed. Renal involvement and flares during pregnancy were associated with both poor fetal and maternal outcomes. The beneficial effect of HCQ in lupus pregnancy was not demonstrated clearly, but there was a trend in favor of better pregnancy outcomes among the HCQ users. Age ≥ 25 years at conception, the presence of or ever having renal involvement during pregnancy, presence of SLE flare and hematologic involvement during pregnancy were predicting factors for poor pregnancy outcomes. Cutaneous vasculitis, and renal, hematologic and mucocutaneous involvement during pregnancy predicted SLE flare. The effect of APL/LAC on pregnancy outcomes in Thai populations needs further investigations.
Acknowledgments
The authors thank Mrs. Waraporn Sukitawut, Ms. Saowanee Pantana and Ms. Phimwalan Konkaeo for their secretarial assistance.
Author contributions
Conceptualization: Worawit Louthrenoo, Thananant Trongkamolthum, Nuntana Kasitanon, Antika Wongthanee.
Data curation: Worawit Louthrenoo, Thananant Trongkamolthum.
Formal analysis: Worawit Louthrenoo, Antika Wongthanee.
Investigation: Worawit Louthrenoo, Thananant Trongkamolthum.
Methodology: Worawit Louthrenoo, Thananant Trongkamolthum.
Supervision: Worawit Louthrenoo.
Validation: Worawit Louthrenoo, Antika Wongthanee.
Visualization: Worawit Louthrenoo, Antika Wongthanee.
Writing – original draft: Worawit Louthrenoo, Thananant Trongkamolthum.
Writing – review & editing: Worawit Louthrenoo, Thananant Trongkamolthum, Nuntana Kasitanon, Antika Wongthanee.
Abbreviations: 95% CI = 95% confidence intervals, ACL = anti-cardiolipin antibodies, ACR = American College of Rheumatology, ANA = antinuclear antibodies, Anti-dsDNA = anti-double stranded DNA antibodies, Anti-Ro = anti-Ro antibodies, Anti-Sm = anti-Smith antibodies, AOR = adjusted odds ratio, APL = anti-phospholipid antibodies, APO = adverse pregnancy outcomes, APS = anti-phospholipid syndrome, HCQ = hydroxychloroquine, HELLP syndrome = hemolysis, elevated liver enzymes, and low platelet count syndrome, IM drugs = immunosuppressive drugs, LAC = lupus coagulants, LBW = low birth weight, mSLEDAI-2K = modified Systemic Lupus Erythematosus Disease Activity Index-2000, OR = odds ratio, PGA = physician global assessment, PIH = pregnancy induced hypertension, PPH = post-partum hemorrhage, PROM = premature rupture of membrane, SDI = the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, SFI = the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE flare index, SGA = small for gestational age, SLE = systemic lupus erythematosus, VLBW = very low birth weight.
How to cite this article: Louthrenoo W, Trongkamolthum T, Kasitanon N, Wongthanee A. Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus: a STROBE-compliant study. Medicine. 2021;100:5(e24553).
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
∗ twin pregnancy.
† maternal complications (PROM + oligohydramnios = 1, PROM + post-partum hemorrhage = 1, PROM + PIH = 1, PIH + eclampsia = 1), ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, LBW = low birth weight, PIH = pregnancy induced hypertension, PPH = post-partum hemorrhage, PROM = premature rupture of membrane, SGA = small for gestational age.
∗ number of positive tests/number tested.
† excluding hydroxychloroquine, −6 M = 6 months prior to conception, ACR = American College of Rheumatology, ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, APS = anti-phospholipid syndrome, BW = birth weight, LBW = low birth weight, SDI = Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index, mSLEDAI-2K = modified systemic lupus erythematosus disease activity index – 2000, SGA = small for gestational age.
∗ number of positive tests/number tested.
† excluding hydroxychloroquine, −6 M = 6 months prior to conception, ACR = American College of Rheumatology, ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, APS = anti-phospholipid syndrome, SDI = Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index, SLEDAI-2K = systemic lupus erythematosus disease activity index – 2000.
a AOR (95% CI) = 4.15 (1.10–15.72), P = .036.
b AOR (95% CI) = 9.21 (1.03–82.51), P = .047.
c AOR (95% CI) = 3.89 (0.99–15.20), P = .051.
d AOR (95% CI) = 0.11 (0.02–0.85), P = .034.
e AOR (95% CI) = 6.0 (1.77–20.52), P = .004.
f AOR (95% CI) = 4.46 (1.44–13.78), P = .009.
g AOR (95% CI) = 10.01 (3.07–32.62), P < .001.
HCQ = hydroxychloroquine, IM drugs = immunosuppressive drugs, excluding HCQ, n = number of pregnancies with positive conditions, N1 = number of pregnancies, N2 = number of pregnancies with live births.
a AOR (95% CI) = 8.45 (1.58–45.30), P = .013.
b AOR (95% CI) = 9.24 (1.70–50.24), P = .010.
c AOR (95% CI) = 0.08 (0.01–0.68), P = .021.
d AOR (95% CI) = 33.87 (1.05–1,094.65), P = .047.
e AOR (95% CI) = 31.89 (6.66–152.69), P < .001.
f AOR (95% CI) = 9.17 (1.83–45.90), P = .007.
g AOR (95% CI) = 128.00 (4.60–3564.46), P = .004.
HCQ = hydroxychloroquine, IM drugs = immunosuppressive drugs, excluded HCQ, n = number of pregnancies with positive conditions, N1 = number of pregnancies, N2 = number of pregnancies with live birth. | 1.25 kg. | Weight | CC BY-NC | 33592909 | 19,221,827 | 2021-02-05 |
What was the administration route of drug 'MYCOPHENOLATE MOFETIL'? | Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus: A STROBE-compliant study.
Studies on predicting factors for adverse pregnancy outcomes (APOs) in Thai patients with systemic lupus erythematosus (SLE) are limited. This retrospective observation study determined APOs and their predictors in Thai patients with SLE.Medical records of pregnant SLE patients in a lupus cohort, seen from January 1993 to June 2017, were reviewed.Ninety pregnancies (1 twin pregnancy) from 77 patients were identified. The mean age at conception was 26.94 ± 4.80 years. At conception, 33 patients (36.67%) had active disease, 23 (25.56%) hypertension, 20 (22.22%) renal involvement, and 6 of 43 (13.95%) positive anti-cardiolipin antibodies or lupus anti-coagulants, and 37 (41.11%) received hydroxychloroquine. Nineteen patients (21.11%) had pregnancy loss. Of 71 successful pregnancies, 28 (31.11%) infants were full-term, 42 (46.67%) pre-term and 1 (11.11%) post-term; 19 (26.39%) were small for gestational age (SGA), and 38 (52.58%) had low birth weight (LBW). Maternal complications occurred in 21 (23.33%) pregnancies [10 (11.11%) premature rupture of membrane (PROM), 8 (8.89%) pregnancy induced hypertension (PIH), 4 (4.44%) oligohydramnios, 2 (2.22%) post-partum hemorrhage, and 1 (1.11%) eclampsia]. Patients aged ≥ 25 years at pregnancy and those ever having renal involvement had predicted pregnancy loss with adjusted odds ratio (AOR) [95% CI] of 4.15 [1.10-15.72], P = .036 and 9.21 [1.03-82.51], P = .047, respectively. Renal involvement predicted prematurity (6.02 [1.77-20.52, P = .004), SGA (4.46 [1.44-13.78], P = .009), and LBW in infants (10.01 [3.07-32.62], P < .001). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception protected against prematurity (0.11 [0.02-0.85], P = .034). Flares and hematologic involvement predicted PROM (8.45 [1.58-45.30], P = .013) and PIH (9.24 [1.70-50.24], P = .010), respectively. Cutaneous vasculitis (33.87 [1.05-1,094.65], P = .047), and renal (31.89 [6.66-152.69], P < .001), mucocutaneous (9.17 [1.83-45.90], P = .007) and hematologic involvement (128.00 [4.60-3,564.46], P = .004) during pregnancy predicted flare; while prednisolone (>10 mg/day) and immunosuppressive drug use at conception reduced that risk (0.08 [0.01-0.68, P = .021).APOs remain a problem in Thai pregnant SLE patients. Renal involvement and SLE flares were associated with the risk of APOs.
1 Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ systems, characterized by remission and relapse. The disease predominantly affects women of child bearing age. Pregnancy in SLE patients is a challenging issue in clinical practice because of its association with increasing adverse outcomes in both mother and fetus.[1,2] Pregnant women with SLE have a reportedly higher rate of spontaneous abortion, fetal loss, intra-uterine growth retardation, pre-term delivery, pregnancy induced hypertension (PIH), pre-eclampsia and flares. Furthermore, pregnancy in SLE patients can cause disease exacerbation or flare, which often requires increasing doses of corticosteroids and/or immunosuppressive drugs that can have adverse effects on mother and fetus.[3,4] Thus, it is suggested that pregnancy in SLE patients should be avoided if the patients have had active severe disease within the previous 6 months, or significant heart, lung, renal and central nervous system involvement.[3,4]
With progress made in understanding the clinical course of SLE, standard instruments that determine disease activity and flares have been developed, as well as progression in medical treatment that results in improved obstetrics care of pregnant SLE patients.[3,5] Pregnancy outcomes in SLE patients have been reported widely, however, data on pregnancy outcomes from Asian countries are very limited.[6–11]
The purpose of this study was to determine pregnancy outcomes and identify independent predicting factors for adverse pregnancy outcomes (APOs) from a lupus cohort of Thai pregnant patients with SLE.
2 Patients and methods
2.1 Patients and data source
The medical records of SLE patients in a lupus cohort seen between January 1993 and June 2017 at the Division of Rheumatology, Faculty of Medicine, Chiang Mai University, Thailand were reviewed. SLE was diagnosed according to the 1997 updating the American College of Rheumatology (ACR) revised criteria for the classification of SLE.[12] Pregnant SLE patients were identified. Clinical manifestations, laboratory investigations, treatment, and SLE disease activity were recorded from 6 months prior to conception (−6 M) until 6 weeks after termination of pregnancy or delivery or the post-partum period. Pregnancy data were recorded at the time of conception or when the pregnancy was documented. The data were captured at −6 M, 3 months prior to conception (−3 M), at the time of conception, 1st trimester, 2nd trimester, 3rd trimester, and the post-partum period. If the patients had more than 1 visit during each period, the mean SLE disease activity of each period was used for statistical analysis. Laboratory investigations, including complete blood counts, urine analysis, and renal and liver functions were recorded routinely. The 24-hour urine protein creatinine ratio (24hour UPCI) [urine protein in gm/day to urine creatinine in gm/day] was determined only in cases with lupus nephritis (urine protein >0.5 gm/day). SLE patients were followed up usually in the clinic at 1 to 3 month intervals, depending on SLE disease activity or other clinical encounters. If the patients had more than 1 pregnancy, each one was considered as a separate observation and counted as an individual case.
Patients in the clinic should have been in clinical remission or have stable low disease activity (prednisolone ≤10 mg/day without immunosuppressive drugs other than anti-malarial medication) for a minimum of 12 months to allow for pregnancy to occur. Those who developed mild to moderate flares during pregnancy were administered prednisolone at a dosage of up to 0.50 mg/kg/day, and those with severe flares received >0.50 to 1.00 mg/kg/day. Anti-malarial medication was given according to clinical indications, e.g., skin rashes, oral ulcers or alopecia. Immunosuppressive drugs, particularly azathioprine and cyclosporine, were given to cases of severe flares. Cases in which the patients received methotrexate, cyclophosphamide or mycophenolate mofetil at the time of pregnancy, had these immunosuppressive drugs discontinued immediately and replaced with azathioprine or cyclosporine.
2.2 SLE disease activity and flare assessment
The modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K)[13] was used in this study to determine SLE disease activity (as anti-dsDNA and complements were not routinely available at this institution). The severity of SLE disease activity was classified according to that of Abrahamowicz et al,[14] but the mSLEDAI-2K instrument was used instead of the original SLEDAI-2K; remission [mSLEDAI-2K = 0], mild disease activity [mSLEDAI-2K = 1–5], moderate disease activity [mSLEDAI-2K = 6–10], high disease activity [mSLEDAI-2K = 11–19] and very high disease activity [mSLEDAI-2K = ≥20]). The severity of SLE flare (mild or moderate flare and severe flare) followed the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE flare index (SFI).[15] As the physician global assessment (PGA) was not recorded routinely, the SFI was modified by excluding the PGA items (mSFI). Organ damage accrual was determined using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).[16]
2.3 Pregnancy outcomes
The definition of maternal complications (premature rupture of membrane [PROM], oligohydramnios, pregnancy induced hypertension [PIH], pre-eclampsia, eclampsia, and direct and indirect maternal death), and fetal outcomes (pregnancy loss, miscarriage or spontaneous abortion, intra-uterine fetal death, medical termination of pregnancy, pre-term delivery, term delivery, post-term delivery, neonatal death, small for gestational age [SGA], and infant birth weight) followed that of standard references.[17]
2.4 Ethical statement
This study was performed in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This study was approved by the Ethic Committee of the Faculty of Medicine, Chiang Mai University (no. 215/2017).
2.5 Statistical analysis
STATA 14.2 computer software (Stata Corporation, Texas USA) was used for data processing and statistical analysis. As some patients had more than 1 pregnancy, each one was considered individually for statistical analysis. Continuous variables were presented as mean ± standard deviation (SD) or median (min-max), with categorical variables presented as percent. The Student t test and Wilcoxon rank sum test were used to determine the differences between 2 independent samples of continuous variables. One-way analysis of variance (ANOVA) and the Kruskal–Wallis test were used for more than 2 samples, with normal and non-normal distribution, respectively. The Chi-Squared test or Fisher exact test was used to determine associations among the categorical variables, where appropriate. Firth's logistic regression was used to predict the odds ratio (OR) and 95% confidence intervals (95% CI) when the outcome contained cell counts of zero. Variables with a P value <.20 from univariate analysis were entered into multiple logistic regression analysis, and reported as adjusted odds ratio (AOR) and 95% CI. A P ≤ .05 was considered as being a statistically significant difference.
3 Results
3.1 Demographics and characteristics of pregnant SLE patients
From a cohort of 1167 female SLE patients, 90 pregnancies occurred from 77 patients (1, 2, and 3 pregnancies in 66, 9 and 2 patients, respectively). Their mean age at SLE onset and age at pregnancy was 21.63 ± 5.89 years and 26.94 ± 4.80 years, respectively. Pregnancies occurred at the time of SLE diagnosis, and < 5 years and ≥ 5 years after SLE diagnosis in 7 (7.78%), 49 (54.44%) and 34 (37.78%) pregnancies, respectively. Of the 90 pregnancies, 45 (50.00%), 25 (27.78%), and 20 (22.22%) were the first, second and third or more, respectively. Their mean cumulative ACR classification criteria and SDI score were 5.49 ± 1.15 and 0.40 ± 0.72, respectively. The mean ± SD mSLEDAI-2K score at −6 M and time of conception was 1.72 ± 3.22 and 1.90 ± 3.44, respectively. Active disease at the time of conception (mSLEDAI-2K score ≥ 0) was observed in 33 of 90 pregnancies (36.67%), and all of them were unplanned. Active organ involvement at the time of conception was renal (urine protein creatinine ratio >0.5) in 20 (22.22%) pregnancies, mucocutaneous lesions in 15 (16.67%), cutaneous vasculitis in 2 (2.22%), and arthritis and hematologic abnormalities in 1 (1.11%) of each.
Co-morbidities were seen as follows: hypertension in 23 (25.56%) pregnancies, dyslipidemia in 8 (8.89%), thalassemia in 7 (7.78%), anti-phospholipid syndrome in 3 (3.33%), diabetes mellitus in 1 (1.11%), and others in 19 (21.11%) [hepatitis C virus infection, avascular necrosis of the hip, stroke and atrial secundum defect, and past history of cryptococcal meningitis, pneumocystis jirovecii pneumonia, and past treatment of pulmonary tuberculosis]. None of the patients drank alcohol or smoked.
Antinuclear antibodies (ANA) were observed in 89 pregnancies (98.89%). Anti-double stranded DNA (anti-dsDNA), anti-Smith (anti-Sm), anti-cardiolipin (ACL), lupus coagulants (LAC), and anti-Ro (anti-Ro) antibodies were observed in 50 of 85 (58.82%), 1 of 12 (8.33%), 4 of 58 (6.89%), 3 of 42 (7.14%), and 21 of 46 (45.65%) pregnancies that had been tested, respectively.
Patients in 15 of the 90 pregnancies (16.67%) had not received any specific SLE medication at the time of conception. Patients in 57 (63.33%) of the pregnancies received prednisolone at a dose of ≤10 mg/day, and in 16 (17.78%) at ≥ 10 mg/day, with the mean dosage of 10.77 ± 11.73 mg/day. Patients also received hydroxychloroquine (HCQ) in 37 (41.11%) pregnancies, cyclophosphamide in 6 (6.67%), mycophenolate mofetil in 4 (4.40%), azathioprine in 10 (11.11%), and cyclosporine in 3 (3.33%). Both cyclophosphamide and mycophenolate mofetil were switched to azathioprine or cyclosporine when the pregnancy was documented.
3.2 Overall pregnancy outcomes
Of the 90 pregnancies, 19 (21.11%) were lost (spontaneous abortion in 12 (13.33%) [7 in the 1st trimester and 5 in the 2nd], medical termination in 5 (5.56%) [1 in the 1st trimester and 4 in the 2nd], and dead fetus in the utero (1 in each 2nd and 3rd trimester). Of the 71 (78.89%) successful pregnancies, 28 (31.11%) were full-term, 42 (46.67%) pre-term (1 twin pregnancy), and 1 (1.11%) was a post-term delivery, resulting in 72 live born infants. Mode of delivery among the live births were vaginal in 52 (73.24%) and cesarean section in 19 (26.76%). The mean ± SD duration of pregnancy with live born infants was 35.76 ± 3.58 weeks. The mean ± SD weight of the 72 live born infants was 2,367.33 ± 640.30 gm (range 720–3853 gm), with normal birth weight (≥2500 gm), low birth weight (LBW) [1500–2499 gm], and very low birth weight (VLBW) [<1500 gm] in 34 (47.22%), 30 (41.67%) and 8 (11.11%) infants, respectively. SGA infants occurred in 19 live born infants (26.39%). There was 1 neonatal death (1.11%). No infants had congenital anomalies or completed heart block.
Maternal complications occurred in 21 (23.33%) pregnancies. PROM occurred in 10 (11.11%) pregnancies, PIH in 8 (8.89%), oligohydramnios in 4 (4.44%), post-partum hemorrhage in 2 (2.22%), and eclampsia in 1 (1.11%). One concomitant PROM and oligohydramnios, PROM and post-partum hemorrhage, PROM and PIH, and PIH and eclampsia occurred in each pregnancy. There were no cases of anti-partum hemorrhage, post-partum endometritis, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), pre-eclampsia or maternal death. Thirty seven flares (41.11%) were mild to moderate and severe in 9 (24.32%) and 28 (75.68%) pregnancies, respectively.
3.3 Effect of renal involvement, hypertension, presence of anti-cardiolipin antibodies and/or lupus anti-coagulants and SLE flares on pregnancy outcomes
The effects of renal involvement, hypertension, and the presence of ACL/LAC and SLE flares on pregnancy outcomes were determined and are shown in Table 1.
Table 1 Effect of active renal involvement during pregnancy, hypertension at the time of conception, presence of anti-phospholipid antibodies and SLE flares during pregnancy on pregnancy outcomes.
Renal involvement Hypertension ACL/LAC Flares
Yes No P value Yes No P value Yes No P value Yes No P value
Successful pregnancy, n (%) 30 (75.00) 41 (82.00) .419 16 (69.57) 55 (82.09) .204 4 (66.67) 32 (86.49) .248 32 (86.49) 39 (73.58) .140
Pregnancy duration, in weeks, mean ± SD 34.34 ± 4.50 36.80 ± 2.26 .009 35.60 ± 2.47 35.81 ± 3.86 .838 38.50 ± 2.52 36.20 ± 3.45 .209 34.43 ± 3.91 36.85 ± 2.90 .004
Fetal weight, in grams, mean ± SD 2,029.52 ± 611.82 2,622.76 ± 540.06 <.001 2,147.65 ± 580.34 2,435.24 ± 647.59 .106 2,680.00 ± 557.32 2,379.94 ± 749.66 .447 2097.58 ± 615.13 2595.59 ± 575.07 .001
Fetal outcomes
Live birth, n (%) 31 (75.61)∗ 41 (82.00) .456 17 (70.83)∗ 55 (82.09) .244 4 (66.67) 32 (86.49) .248 33 (86.84)∗ 39 (73.58) .125
Term, n (%) 6 (15.00) 22 (44.00) .003 7 (30.43) 21 (31.34) .935 3 (50.00) 14 (37.84) .666 9 (24.32) 19 (35.85) .245
Pre-term, n (%) 24 (58.54)∗ 19 (38.00) .051 10 (41.67)∗ 33 (49.25) .523 1 (16.67) 17 (45.95) .177 24 (63.16)∗ 19 (35.85) .010
Post-term, n (%) 1 (2.50) 0 .444 0 1 (1.49) >.999 0 1 (2.70) >.999 0 1 (1.89) >.999
Total fetal loss, n (%) 10 (25.00) 9 (18.00) .419 7 (30.43) 12 (17.91) .204 2 (33.33) 5 (13.51) .248 5 (13.51) 14 (26.42) .140
Spontaneous abortion, n (%) 6 (15.00) 6 (12.00) .677 4 (17.39) 8 (11.94) .507 1 (16.67) 4 (10.81) .547 3 (8.11) 9 (16.98) .223
Medical termination, n (%) 2 (5.00) 3 (6.00) >.999 2 (8.70) 3 (4.48) .599 1 (16.67) 1 (2.70) .262 1 (2.70) 4 (7.55) .645
Dead fetus in the utero, n (%) 2 (5.00) 0 .195 1 (4.35) 1 (1.49) .448 0 0 1 (2.70) 1 (1.89) >.999
Neonatal death, n (%) 1 (2.50) 0 .444 1 (4.35) 0 .256 0 1 (2.70) >.999 1 (2.70) 0 .411
SGA, n (%) 13 (32.50) 6 (12.00) .018 7 (30.43) 12 (17.91) .204 1 (16.67) 12 (32.43) .649 11 (29.73) 8 (15.09) .094
LBW (< 2500 grams), n (%) 25 (60.98)∗ 13 (26.00) .001 11 (45.83)∗ 27 (40.30) .637 1 (16.67) 18 (48.65) .143 23 (60.53)∗ 15 (28.30) .002
Maternal complications†, n (%) 30 (75.00) 15 (30.00) <.001 16 (69.57) 29 (43.28) .030 2 (33.33) 18 (48.65) .669 37 (100.00) 8 (15.09) <.001
PROM, n (%) 6 (15.00) 4 (8.00) .294 1 (4.35) 9 (13.43) .232 0 4 (10.81) >.999 8 (21.62) 2 (3.77) .008
Oligohydramnios, n (%) 3 (7.50) 1 (2.00) .319 1 (4.35) 3 (4.48) >.999 0 2 (5.41) >.999 2 (5.41) 2 (3.77) >.999
PPH, n (%) 0 2 (4.00) .501 0 2 (2.99) >.999 0 1 (2.70) >.999 0 2 (3.77) .510
PIH, n (%) 5 (12.50) 3 (6.00) .282 1 (4.35) 7 (10.45) .375 0 3 (8.11) >.999 5 (13.51) 3 (5.66) .198
Eclampsia, n (%) 0 1 (2.00) >.999 0 1 (1.49) >.999 0 1 (2.70) >.999 0 1 (1.89) >.999
Flares, n (%) 27 (67.50) 10 (20.00) <.001 14 (60.87) 23 (34.33) .026 2 (33.33) 14 (37.84) >.999
Forty pregnancies were shown to have active nephritis during pregnancy. Active renal involvement occurred in 30, 30, and 26 pregnancies during the 1st, 2nd, and 3rd trimester, respectively, which was significantly higher than the 20 pregnancies seen at the time of conception (P < .001). When compared to patients without renal involvement during pregnancy, those with it had significantly shorter mean pregnancy duration (34.34 ± 4.40 weeks vs 36.80 ± 2.26 weeks, P = .003), lower fetal birth weight among live births (2029.52 ± 611.82 gm vs 2622.76 ± 540.06 gm, P < .001), and a higher proportion of LBW infants (60.98% vs 26.00%, P < .001), and SGA infants (32.50% vs 12.00%, P = .018). Although the proportion among live birth infants was not different, those with renal involvement had a significantly lower proportion of full-term infants (15.00% vs 44.00%, P = .003) and almost significantly higher proportion of pre-term infants (58.54% vs 38.00%, P = .051). There was no statistically significant difference in fetal loss among the 2 groups. The maternal complications in those with renal involvement during pregnancy were significantly higher (75.00% vs 30.00%, P < .001), which was due to a higher proportion of patients with SLE flare (67.50% vs 20.00%, P < .001). Other maternal complications, including PROM, oligohydramnios and PIH, also were higher proportionally, but they did not reach statistical significance.
Overall, there were no statistically significant differences in adverse fetal outcomes among patients with or without hypertension during pregnancy. However, pregnancy outcomes among patients with hypertension tended to have a lower proportion of live birth infants, and higher proportion of fetal loss (both spontaneous and medical terminations), SGA and LBW among full-term infants, and a lower mean fetal birth weight. Maternal complications were significantly higher in patients with hypertension (69.57% vs 43.28%, P = .030), which was due mainly to the higher proportion of those with SLE flares (60.48% vs 34.33%, P = .026). It was interesting that the proportion of PROM and PIH was lower in patients with hypertension, but with no significance.
The effect of anti-cardiolipin antibodies (ACL) and lupus anticoagulant (LAC) tests on pregnancy outcomes also was determined. Unfortunately, these 2 tests were determined in only approximately 50% of the patients. ACA and LAC were positive in a small proportion of the patients (4 of 58 or 6.89% and 3 of 42 or 7.14% of those tested, respectively). Overall, there was no statistically significant difference between either the fetal and maternal outcomes among pregnant patients with positive ACL/LAC or those without; however, those with positive ACL/LAC tended to have a lower proportion of live births and full-term birth infants, and higher proportion of fetal losses. It was interesting that the proportion of SGA, LBW, and maternal complication in the ACL/LAC positive patients also was lower, but without statistical significance. This might be due to the small number of patients in this group.
The effect of flares on pregnancy outcomes also was determined. When compared to SLE patients without flares during pregnancy, those with them had significantly shorter duration of pregnancy (34.43 ± 3.91 weeks vs 36.85 ± 2.90 weeks, P = .004), and lower mean fetal weight among live births (2097.58 ± 615.13 gm vs 2595.59 ± 575.07 gm, P = .001). Although the proportion of live birth infants and fetal loss was no different between the 2 groups, the patients with flares had a significantly higher proportion of pre-term births and LBW infants (63.16% vs 35.85%, P = .010, and 60.53% vs 28.30%, P = .002, respectively). The proportion of SGA infants also was higher, but did not reach statistical significance (29.73% vs 15.09%, P = .094). The adverse maternal outcomes were higher (100.00% vs 15.09%, P < .001), particularly of PROM (21.62% vs 3.77%, P < .008).
3.4 Effect of HCQ used on pregnancy outcomes
The effect of HCQ used during pregnancy on pregnancy outcomes was determined. Overall, there was no statistically significant difference in fetal outcomes among patients who did or did not receive HCQ during pregnancy. However, infants born to mothers who used HCQ tended to have a higher proportion of full term births (37.84% vs 26.42%, P = .249), and lower proportion of SGA (16.22% vs. 24.53%, P = .342) and LBW (36.84% vs 45.28%, P = .421). The proportion of live birth infants and fetal loss was similar between the 2 groups (78.95% vs 79.25%, P = .972, and 21.62% vs. 20.75%, P = .921, respectively). The proportion of maternal complications was lower among patients who received HCQ, and it almost reached statistical significance (37.84% vs 58.49%, P = .054). The proportion of maternal PROM, PIH and flares in the HCQ group also was lower, but did not reach statistical significance (5.41% vs 15.09%, P = .150; 5.41% vs 11.32%, P = .332, and 32.43% vs 47.17%, P = .162, respectively).
3.5 Pregnancy outcomes according to period of pregnancy, and between the first and subsequence pregnancy
The pregnancy outcomes according to the period of pregnancy (1993–2001, 2002–2009, and 2010–2017) were determined. Overall, there was no statistically significant difference in fetal or maternal outcomes between each pregnancy period. However, when comparing the pregnancy outcomes between 2010–2017, 2002–2009, and 1993–2001, fetal outcomes among pregnancies during 2010–2017 tended to have a higher proportion of live births (80.85% vs 76.00% vs 78.95%, P = .890), full-term birth infants (36.17% vs 32.00% vs 16.67%, P = .313), but with a lower proportion of pre-term birth infants (42.55% vs 44.00% vs 63.16%, P = .294), and pregnancy loss (19.15% vs 24.00% vs 22.22%, P = .884). They also had had a higher proportion of SGA and LBW (29.79% vs 16.00% vs 5.56%, P = .070, and 48.94% vs 36.00% vs 31.58%, P = .342, respectively). The proportion of maternal complications was similar (48.94% vs 48.00% vs 55.56%, P = .868); but with a tendency for decreased proportion of PROM (8.51% vs 12.00% vs 16.67%, P = .495), PIH (8.51% vs 4.00% vs 16.67%, P = .382) and SLE flares (38.30% vs 44.00% vs 44.44%, P = .851).
The pregnancy outcomes between patients with a first pregnancy and subsequent pregnancies also were compared. Similarly, there was no significant difference in fetal and maternal outcomes between the 2 groups. However, fetal outcomes in subsequent pregnancy groups tended to have a lower proportion of live births (73.91% vs 84.44%, P = .217), full-term births (24.44% vs 37.78%, P = .172), SGA (17.78% vs 24.44%, P = .438) and LBW infants (36.96% vs 46.67%, P = .348), but higher proportion of fetal loss (26.67% vs 15.56%, P = .197). Maternal complications tended to be lower (46.67% vs 53.33%, P = .527), which was due mainly to decreased proportion of SLE flares (37.78% vs 44.44%, P = .520). The rate of caesarean section was significantly higher among subsequent pregnancies (39.39% vs 15.79%, P = .025).
3.6 Predicting factors for adverse pregnancy outcomes
In order to determine independent predicting factors for APOs, the clinical characteristics that associated with adverse fetal outcomes (pregnancy loss, prematurity, SGA and LBW), and adverse maternal outcomes (PROM, PIH and flare) were compared and are shown in Tables 2 and 3, respectively.
Table 2 Comparison of clinical characteristics of adverse fetal outcomes in pregnant SLE patients.
Successful pregnancy Pregnancy loss Pre-maturity Full term + post term SGA Non-SGA LBW Normal BW
Characteristics (n = 71) (n = 19) P value (n = 42) (n = 29) P value (n = 19) (n = 52) P value (n = 37) (n = 34) P value
Age at pregnancy (in years), mean ± SD 26.30 ± 4.55 29.31 ± 5.09 .014 26.46 ± 4.73 26.07 ± 4.34 .726 25.09 ± 3.85 26.74 ± 4.73 .178 26.12 ± 4.61 26.50 ± 4.54 .726
Disease duration prior to conception (in years), mean ± SD 4.92 ± 5.01 6.99 ± 5.37 .081 4.38 ± 3.96 5.71 ± 6.21 .574 5.20 ± 4.26 4.82 ± 5.29 .451 4.54 ± 4.08 5.34 ± 5.89 .954
Co-morbidities
Hypertension, n (%) 16 (22.54) 7 (36.84) .204 9 (21.43) 7 (24.14) .788 7 (36.84) 9 (17.31) .081 10 (27.03) 6 (17.65) .345
Diabetes, n (%) 1 (1.41) 0 >.999 1 (2.38) 0 >.999 1 (5.26) 0 .268 1 (2.70) 0 >.999
Dyslipidemia, n (%) 5 (7.04) 3 (15.79) .234 3 (7.14) 2 (6.90) >.999 4 (21.05) 1 (1.92) .016 4 (10.81) 1 (2.94) .359
APS, n (%) 2 (2.82) 1 (5.26) .513 0 2 (6.90) .163 0 2 (3.85) >.999 0 2 (5.88) .226
ANA positive, n (%) 70 (98.59) 19 (100.00) >.999 41 (97.62) 29 (100.00) >.999 19 (100.00) 51 (98.08) >.999 37 (100.00) 33 (97.06) .479
Anti-dsDNA, n (%)∗ 41/67 (61.19) 9/18 (50.00) .392 26/40 (65.00) 15/27 (55.56) .436 13/19 (68.42) 28/48 (58.33) .445 25/37 (67.57) 16/30 (53.33) .234
Anti-Sm, n (%)∗ 0/11 1/1 (100.00) .083 0/7 0/4 0/2 0/9 0/6 0/5
ACL/LAC, n (%)∗ 4/36 (11.11) 2/7 (28.57) .248 1/18 (5.56) 3/18 (16.67) .603 1/13 (7.69) 3/23 (13.04) >.999 1/19 (5.26) 3/17 (17.65) .326
Anti-Ro, n (%)∗ 16/38 (42.11) 5/8 (62.50) .293 7/17 (41.18) 9/21 (42.86) .917 6/13 (46.15) 10/25 (40.00) .715 11/23 (47.83) 5/15 (33.33) .376
Anti-La, n (%)∗ 16/38 (42.11) 4/9 (44.44) .898 7/17 (41.18) 9/21 (42.86) .917 6/13 (46.15) 10/25 (40.00) .715 11/23 (47.83) 5/15 (33.33) .376
Pregnancy loss (ever), n (%) 23 (32.39) 9 (47.37) .226 12 (28.57) 11 (37.93) .407 6 (31.58) 17 (32.69) .929 11 (29.73) 12 (35.29) .617
Cumulative number of ACR criteria, mean ± SD 5.46 ± 1.11 5.58 ± 1.35 .704 5.38 ± 1.17 5.59 ± 1.02 .446 5.42 ± 1.02 5.48 ± 1.15 .842 5.35 ± 1.06 5.59 ± 1.16 .371
Disease activity (mSLEDAI-2K) at −6M, mean ± SD 1.34 ± 2.43 3.16 ± 5.05 .325 1.36 ± 2.44 1.31 ± 2.46 .960 1.42 ± 2.48 1.31 ± 2.44 .874 1.38 ± 2.53 1.29 ± 2.36 .933
Disease activity (mSLEDAI-2K) at conception, mean ± SD 1.58 ± 2.74 3.16 ± 5.22 .562 1.81 ± 2.98 1.24 ± 2.36 .385 2.16 ± 2.99 1.36 ± 2.64 .222 1.92 ± 3.22 1.20 ± 2.08 .566
Remission, n (%) 45 (63.38) 12 (63.16) .321 25 (59.52) 20 (68.97) .629 10 (52.63) 35 (67.31) .444 23 (62.16) 22 (64.71) .955
Mild, n (%) 19 (26.76) 3 (15.79) 13 (30.95) 6 (20.69) 6 (31.58) 13 (25.00) 10 (27.03) 9 (26.47)
Moderate and high, n (%) 7 (9.86) 4 (21.05) 4 (9.52) 3 (10.34) 3 (15.79) 4 (7.69) 4 (10.81) 3 (8.82)
SDI score at conception, mean ± SD 0.35 ± 0.66 0.58 ± 0.90 .400 0.36 ± 0.62 0.34 ± 0.72 .612 0.21 ± 0.42 0.40 ± 0.72 .463 0.24 ± 0.55 0.47 ± 0.75 .169
Active organ involvement during pregnancy
Renal 30 (42.25) 10 (52.63) .419 23 (54.76) 7 (24.14) .010 13 (68.42) 17 (32.69) .007 24 (64.86) 6 (17.65) <.001
Mucocutaneous 23 (32.39) 4 (21.05) .338 12 (28.57) 11 (37.93) .407 4 (21.05) 19 (36.54) .217 9 (24.32) 14 (41.18) .130
Vasculitis 2 (2.82) 1 (5.26) .513 1 (2.38) 1 (3.45) >.999 1 (5.26) 1 (1.92) .466 1 (2.70) 1 (2.94) >.999
Arthritis 2 (2.82) 0 >.999 2 (4.76) 0 .510 0 2 (3.85) >.999 1 (2.70) 1 (2.94) >.999
Hematologic 8 (11.27) 0 .125 6 (14.29) 2 (6.90) .333 4 (21.05) 4 (7.69) .197 5 (13.51) 3 (8.82) .532
Medication at conception
Prednisolone, n (%) 56 (78.87) 17 (89.47) .294 32 (76.19) 24 (82.76) .505 15 (78.95) 41 (78.85) .993 31 (83.78) 25 (73.53) .290
Dose (in mg/day), mean ± SD 9.11 ± 9.38 16.25 ± 16.58 .058 9.53 ± 9.56 8.54 ± 9.32 .412 12.50 ± 12.32 7.86 ± 7.88 .162 9.11 ± 9.39 9.10 ± 9.57 .823
Prednisolone >10 mg/day 10 (14.08) 6 (31.58) .076 6 (14.29) 4 (13.79) .953 5 (26.32) 5 (9.62) .073 6 (16.22) 4 (11.76) .590
Hydroxychloroquine, n (%) 29 (40.85) 8 (42.11) .921 15 (35.71) 14 (48.28) .290 6 (31.58) 23 (44.23) .337 13 (35.14) 16 (47.06) .307
Dose (in mg/day), mean ± SD 191.38 ± 86.67 256.25 ± 129.39 .144 183.33 ± 79.43 200.00 ± 96.08 .762 166.67 ± 51.64 197.83 ± 93.52 .533 165.38 ± 55.47 212.50 ± 102.47 .275
Immunosuppressive drug† 18 (25.35) 4 (21.05) .699 10 (23.81) 8 (27.59) .719 5 (26.32) 13 (25.00) .910 12 (32.43) 6 (17.65) .153
Mycophenolate mofetil, n (%) 4 (5.63) 0 .575 2 (4.76) 2 (6.90) >.999 1 (5.26) 3 (5.77) >.999 3 (8.11) 1 (2.94) .615
Cyclophosphamide, n (%) 3 (4.23) 3 (15.79) .106 3 (7.14) 0 .265 1 (5.26) 2 (3.85) >.999 3 (8.11) 0 .241
Azathioprine, n (%) 10 (14.08) 0 .083 5 (11.90) 5 (17.24) .525 3 (15.79) 7 (13.46) .803 6 (16.22) 4 (11.76) .590
Cyclosporine, n (%) 2 (2.82) 1 (5.26) .513 0 2 (6.90) .163 0 2 (3.85) >.999 1 (2.70) 1 (2.94) >.999
Flare during pregnancy 32 (45.07) 5 (26.32) .140 23 (54.76) 9 (31.03) .048 11 (57.89) 21 (40.38) .189 22 (59.46) 10 (29.41) .011
Table 3 Comparison of clinical characteristics of adverse maternal outcomes in pregnant SLE patients.
Premature rupture of membrane Pregnancy induced hypertension Flares
Characteristics Yes (n = 10) No (n = 80) P value Yes (n = 8) No (n = 82) P value Yes (n = 37) No (n = 53) P value
Age at pregnancy (in years), mean ± SD 28.85 ± 4.38 26.70 ± 4.82 .182 25.92 ± 3.65 27.03 ± 4.90 .535 26.89 ± 4.75 26.97 ± 4.88 .937
Disease duration prior to conception (in years), mean ± SD 3.81 ± 3.06 5.55 ± 5.31 .521 4.67 ± 6.25 5.43 ± 5.04 .257 5.67 ± 5.45 5.14 ± 4.92 .608
Co-morbidities
Hypertension, n (%) 1 (10.00) 22 (27.50) .232 1 (12.50) 22 (26.83) .375 14 (37.84) 9 (16.98) .026
Diabetes, n (%) 0 1 (1.25) >.999 0 1 (1.22) >.999 0 1 (1.89) >.999
Dyslipidemia, n (%) 0 8 (10.00) .295 0 8 (9.76) .355 3 (8.11) 5 (9.43) .828
APS, n (%) 0 3 (3.75) >.999 0 3 (3.66) >.999 2 (5.41) 1 (1.89) .566
ANA positive, n (%) 10 (100.00) 79 (98.75) >.999 7 (87.50) 82 (100.00) .089 37 (100.00) 52 (98.11) >.999
Anti-dsDNA, n (%)∗ 5/9 (55.56) 45/76 (59.21) .833 5/7 (71.43) 45/78 (57.69) .479 20/35 (57.14) 30/50 (60.00) .792
Anti-Sm, n (%)∗ 0/1 1/11 (9.09) >.999 0/1 1/11 (9.09) >.999 0/4 1/8 (12.50) >.999
ACL/LAC, n (%)∗ 0/4 6/39 (15.38) >.999 0/3 6/40 (15.00) >.999 2/16 (12.50) 4/27 (14.81) >.999
Anti-Ro, n (%)∗ 1/4 (25.00) 20/42 (47.62) .614 2/4 (50.00) 19/42 (45.24) >.999 6/15 (40.00) 15/31 (48.39) .592
Anti-La, n (%)∗ 1/4 (25.00) 19/43 (44.19) .626 2/4 (50.00) 18/43 (41.86) >.999 6/15 (40.00) 14/32 (43.75) .808
Pregnancy loss (ever), n (%) 3 (30.00) 29 (36.25) .697 2 (25.00) 30 (36.59) .513 9 (24.32) 23 (43.40) .063
Cumulative number of ACR criteria, mean ± SD 5.30 ± 1.06 5.51 ± 1.17 0.586 5.62 ± 0.52 5.48 ± 1.20 .518 5.54 ± 1.14 5.45 ± 1.17 .725
Disease activity (mSLEDAI-2K) at -6M, mean ± SD 0.40 ± 1.26 1.89 ± 3.35 .116 0.25 ± 0.71 1.86 ± 3.33 .163 1.70 ± 3.44 1.74 ± 3.09 .696
Disease activity (mSLEDAI-2K) at conception, mean ± SD 0.70 ± 1.34 2.06 ± 3.59 .400 1.00 ± 2.14 2.00 ± 3.54 .454 2.16 ± 3.92 1.74 ± 3.09 .624
Remission, n (%) 7 (70.00) 50 (62.50) 0.450 6 (75.00) 51 (62.20) .704 22 (59.46) 35 (66.04) 0.816
Mild, n (%) 3 (30.00) 19 (23.75) 1 (12.50) 21 (25.61) 10 (27.03) 12 (22.64)
Moderate and high, n (%) 0 11 (13.75) 1 (12.50) 10 (12.20) 5 (13.51) 6 (11.32)
SDI score at conception, mean ± SD 0.50 ± 0.85 0.39 ± 0.70 .728 0 ± 0 0.44 ± 0.74 .079 0.54 ± 0.80 0.30 ± 0.64 .120
Active organ involvement during pregnancy
Renal 6 (60.00) 34 (42.50) .294 5 (62.50) 35 (42.68) .282 27 (72.97) 13 (24.53) <.001
Mucocutaneous 4 (40.00) 23 (28.75) .464 4 (50.00) 23 (28.05) .234 17 (45.95) 10 (18.87) .006
Vasculitis 0 3 (3.75) >.999 0 3 (3.66) >.999 3 (8.11) 0 .066
Arthritis 0 2 (2.50) >.999 0 2 (2.44) >.999 1 (2.70) 1 (1.89) >.999
Hematologic 2 (20.00) 6 (7.50) .190 3 (37.50) 5 (6.10) .003 8 (21.62) 0 <.001
Medication at conception
Prednisolone, n (%) 8 (80.00) 65 (81.25) .924 4 (50.00) 69 (84.15) .039 29 (78.38) 44 (83.02) .580
Dose (in mg/day), mean ± SD 5.94 ± 2.65 11.36 ± 12.78 .423 19.38 ± 27.26 10.27 ± 10.41 .755 8.88 ± 7.89 12.02 ± 13.63 .958
Prednisolone >10 mg/day 0 16 (20.00) .119 1 (12.50) 15 (18.29) .683 5 (13.51) 11 (20.75) .377
Hydroxychloroquine, n (%) 2 (20.00) 35 (43.75) .150 2 (25.00) 35 (42.68) .332 12 (32.43) 25 (47.17) .162
Dose (in mg/day), mean ± SD 125.00 ± 106.07 210.00 ± 98.37 .223 150.00 ± 70.71 208.57 ± 100.36 .382 208.33 ± 129.39 204.00 ± 84.06 .797
Immunosuppressive drug† 2 (20.00) 20 (25.00) .729 0 22 (26.83) .092 7 (18.92) 15 (28.30) .308
Mycophenolate mofetil, n (%) 1 (10.00) 3 (3.75) .381 0 4 (4.88) >.999 2 (5.41) 2 (3.77) >.999
Cyclophosphamide, n (%) 0 6 (7.50) .370 0 6 (7.32) .428 1 (2.70) 5 (9.43) .208
Azathioprine, n (%) 1 (10.00) 9 (11.25) .906 0 10 (12.20) .295 4 (10.81) 6 (11.32) .940
Cyclosporine, n (%) 0 3 (3.75) >.999 0 3 (3.66) >.999 0 3 (5.66) .266
Flare during pregnancy 8 (80.00) 29 (36.25) .008 5 (62.50) 32 (39.02) .198
Factors that might be associated with adverse fetal and maternal outcomes, and those that had a statistical difference with a P value of <.2 in the univariate analysis (Tables 2 and 3) were included in the multiple logistic regression analysis (Tables 4 and 5). Independent predicting factors that increased the risk of fetal loss included age at pregnancy of ≥25 years (AOR [95% CI]) 4.15 [1.10–15.72], P = .036), and ever having renal involvement (9.21 [1.03–82.51], P = .047). Prednisolone used (>10 mg/day) at conception almost reached a predicting factor for fetal loss (3.89 [0.99–15.20], P = .051). Renal involvement during pregnancy independently predicted prematurity (6.02 [1.77–20.52], P = .004), and SGA (4.46 [1.44–13.78], P = .009) and LBW infants (10.01 [3.07–32.62], P < .001). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception independently reduced the risk of prematurity (0.11 [0.02–0.85], P = .034). SLE flares and hematologic involvement during pregnancy independently predicted PROM (8.45 [1.58–45.30], P = .013) and PIH (9.24 [1.70–50.24], P = .010), respectively. Independent predicting factors for SLE flares during pregnancy included the presence of cutaneous vasculitis (AOR [95% CI]) 33.87 [1.05–1094.65], P = .047), and renal (31.89 [6.66–152.69], P < .001), mucocutaneous (9.17 [1.83–45.90], P = .007) and hematologic involvement (128.00 [4.60–3,564.46], P = .004). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception independently reduced the risk of SLE flares during pregnancy (0.08 [0.01–0.68, P = .021).
Table 4 Univariable analysis and multiple logistic regression analysis of factors associated with adverse fetal outcomes in pregnant SLE patients.
Pregnancy loss Prematurity Small for gestational age Low birth weight
Characteristics N1 n OR (95% CI) P value N2 n OR (95% CI) P value n OR (95% CI) P value n OR (95% CI) P value
Age at pregnancy
<25 years 39 4 3.64 35 21 0.93 13 0.34 19 0.84
≥25 years 51 15 (1.01–16.37) .027a 36 21 (0.32–2.67) .886 6 (0.09–1.16) .051 18 (0.30–2.37) .718
Disease duration prior to conception
<5 years 56 8 2.87 48 28 1.11 13 0.95 26 0.78
≥5 years 34 11 (0.90–9.34) .042 23 14 (0.36–3.52) .839 6 (0.25–3.28) .929 11 (0.25–2.36) .617
Hypertension
No 67 12 2.00 55 33 0.86 12 2.79 27 1.73
Yes 23 7 (0.56–6.64) .204 16 9 (0.24–3.15) .788 7 (0.71–10.44) .081 10 (0.48–6.59) .345
Previous pregnancy
0 45 7 1.97 38 21 1.42 11 0.78 21 0.76
≥1 45 12 (0.62–6.61) .196 33 21 (0.49–4.12) .474 8 (0.23–2.56) .655 16 (0.27–2.15) .568
Pregnancy loss (ever)
No 58 10 1.88 48 30 0.65 13 0.95 26 0.78
Yes 32 9 (0.58–5.92) .226 23 12 (0.21–2.03) .408 6 (0.25–3.28) .929 11 (0.25–2.36) .617
Renal disorder (ever)
No 18 1 5.67 17 6 3.67 3 1.96 5 3.49
Yes 72 18 (0.76–249.73) .071b 54 36 (1.02–13.92) .022 16 (0.45–12.00) .330 32 (0.96–14.27) .032
SLE disease activity at conception
Remission and mild 79 15 2.44 64 38 0.91 16 2.25 33 1.25
Moderate and high 11 4 (0.46–11.06) .186 7 4 (0.14–6.76) .909 3 (0.29–14.72) .311 4 (0.19–9.22) .779
Prednisolone >10 mg/day at conception
No 74 13 2.82 61 36 1.04 14 3.36 31 1.45
Yes 16 6 (0.70–10.38) .076c 10 6 (0.22–5.55) .953 5 (0.66–16.66) .073 6 (0.31–7.68) .590
IM drugs used at conception
No 68 15 0.78 53 32 0.82 14 1.07 25 2.24
Yes 22 4 (0.17–2.93) .699 18 10 (0.24–2.83) .719 5 (0.25–3.99) .910 12 (0.65–8.33) .152
Prednisolone >10 mg/day and IM drugs used at conception
No 82 17 1.27 65 40 0.31 17 1.41 34 0.91
Yes 8 2 (0.12–7.98) .778 6 2 (0.03–2.40) .179d 2 (0.12–10.86) .704 3 (0.11–7.33) .914
HCQ used during pregnancy
No 47 11 0.75 36 23 0.67 11 0.67 21 0.60
Yes 43 8 (0.23–2.33) .577 35 19 (0.23–1.93) .410 8 (0.20–2.20) .464 16 (0.21–1.70) .287
Organ involvement during Pregnancy
Cutaneous vasculitis
No 87 18 1.92 69 41 0.68 18 2.83 36 0.92
Yes 3 1 (0.03–38.45) .598 2 1 (0.01–55.50) .789 1 (0.03–226.66) .451 1 (0.01–74.11) .952
Arthritis
No 88 19 0.71 69 40 3.64 19 0.52 36 0.92
Yes 2 0 (0.03–15.47) .829 2 2 (0.17–78.70) .410 0 (0.02–11.28) .676 1 (0.01–74.11) .952
Renal
No 50 9 1.52 41 19 3.80 6 4.46 13 8.62
Yes 40 10 (0.48–4.78) .419 30 23 (1.21–12.72) .010e 13 (1.28–16.62) .007f 24 (2.54–31.31) <.001g
Mucocutaneous
No 63 15 0.56 48 30 0.65 15 0.46 28 0.46
Yes 27 4 (0.12–2.03) .338 23 12 (0.21–2.03) .408 4 (0.10–1.76) .217 9 (0.14–1.42) .130
Hematologic
No 82 19 0.19 63 36 2.25 15 3.20 32 1.61
Yes 8 0 (0.01–3.47) .264 8 6 (0.36–24.23) .333 4 (0.52–19.11) .115 5 (0.28–11.21) .532
Flares during pregnancy
No 53 14 0.44 39 19 2.69 8 2.03 15 3.52
Yes 37 5 (0.11–1.47) .140 32 23 (0.90–8.28) .048 11 (0.62–6.84) .189 22 (1.18–10.70) .011
Table 5 Univariable analysis and multiple logistic regression analysis of factors associated with adverse maternal outcomes in pregnant SLE patients.
Premature rupture of the membrane Pregnancy induced hypertension Flares
Characteristics N n OR 95% CI P value n OR 95% CI P value n OR 95% CI P value
Age at pregnancy
<25 years 39 2 Ref. 4 Ref. 18 Ref.
≥25 years 51 8 3.44 0.62–34.83 .114 4 0.74 0.13–4.31 .690 19 0.69 (0.27–1.76) .395
Disease duration prior to conception
<5 years 56 7 Ref. 6 Ref. 22 Ref.
≥5 years 34 3 0.68 0.10–3.25 .590 2 0.52 0.05–3.17 .435 15 1.22 (0.47–3.15) .652
Hypertension
No 67 9 Ref. 7 Ref. 23 Ref.
Yes 23 1 0.29 0.01–2.36 .232 1 0.39 0.01–3.35 .375 14 2.98 (1.01–8.99) .026
Previous pregnancy
0 45 4 Ref. 4 Ref. 20 Ref.
≥1 45 6 1.58 0.34–8.16 .502 4 1.00 0.17–5.76 >.999 17 0.76 (0.30–1.91) .520
Pregnancy loss (ever)
No 58 7 Ref. 6 Ref. 28 Ref.
Yes 32 3 0.75 0.12–3.63 .697 2 0.58 0.05–3.52 .514 9 0.42 (0.14–1.15) .063
Renal disorder (ever)
No 18 1 Ref. 0 Ref. 5 Ref.
Yes 72 9 2.43 0.30–112.60 .402 8 4.88 0.27–88.50 .284 32 2.08 (0.61–8.19) .199
SLE disease activity at conception
Remission and mild 79 10 Ref. 7 Ref. 32 Ref.
Moderate and high 11 0 0.29 0.02–5.26 .401 1 1.03 0.02–9.54 .980 5 1.22 (0.27–5.27) .755
Prednisolone >10 mg/day at conception
No 74 10 Ref. 7 Ref. 32 Ref.
Yes 16 0 0.19 0.01–3.34 .254 1 0.64 0.01–5.64 .682 5 0.60 (0.15–2.11) .377
IM drugs used at conception
No 68 8 Ref. 8 Ref. 30 Ref.
Yes 22 2 0.75 0.07–4.22 .729 0 0.16 0.01–2.85 .212 7 0.59 (0.18–1.79) .308
Prednisolone >10 mg/day and IM drugs used at conception
No 82 10 Ref. 8 Ref. 36 Ref.
Yes 8 0 0.41 0.02–7.57 .546 0 0.52 0.03–9.74 .659 1 0.18 (0.00–1.55) .085c
HCQ used during pregnancy
No 47 8 Ref. 5 Ref. 20 Ref.
Yes 43 2 0.24 0.02–1.31 .062 3 0.63 0.09–3.50 .542 17 0.88 (0.35–2.22) .771
Organ involvement during pregnancy
Cutaneous vasculitis
No 87 10 Ref. 8 Ref. 34 Ref.
Yes 3 0 1.05 0.05–21.88 .973 0 1.34 0.06–28.11 .852 3 10.86 (0.54–216.71) .119d
Arthritis
No 88 10 Ref. 8 Ref. 36 Ref.
Yes 2 0 1.50 0.07–33.32 .799 0 1.89 0.08–42.79 .688 1 1.44 (0.02–115.53) .796
Renal
No 50 4 Ref. 3 Ref. 10 Ref.
Yes 40 6 2.03 0.44–10.49 .294 5 2.24 0.40–15.24 .282 27 8.31 (2.90–24.34) <.001e
Mucocutaneous
No 63 6 Ref. 4 Ref. 20 Ref.
Yes 27 4 1.65 0.31–7.69 .464 4 2.56 0.43–14.84 .196 17 3.66 (1.29–10.54) .006f
Hematologic
No 82 8 Ref. 5 Ref. 29 Ref.
Yes 8 2 3.08 0.26–21.22 .190 3 9.24 1.07–64.46 .003b 8 30.83 (1.72–553.28) .020g
Flares during pregnancy
No 53 2 Ref. 3 Ref.
Yes 37 8 7.03 1.26–70.80 .008a 5 2.60 0.46–17.73 .198
4 Discussion
Despite significant improvement in medical care for pregnant SLE patients, their APOs are still a significant issue.[5,18] Fetal loss (both spontaneous abortion and intra-uterine death), pre-term birth, intra-uterine growth retardation, SGA and LBW in the fetus, and PIH, pre-eclampsia/eclampsia and flares in the mother are among the major APOs of concern. Reports on SLE patients with APOs varied greatly among studies. This could be explain partly by the difference in time period of the study and ethnicity and socioeconomic status of the patients, as well as SLE disease activity prior to and at the time of conception, organ involvement at conception, rate and organ of flares, and prevalence of ACL/LAC or anti-phospholipid syndrome in the population studied.[1,3,19]
Progressive improvement in pregnancy outcomes over a 25-year period was observed in this study. The proportion of successful pregnancies tended to improve with an increased proportion of full-term births and decreased proportion of pre-term infants. An increased proportion of infants with SGA and LBW had slightly decreased mean fetal birth weight; although all of these changes did not reach statistical significance. The improvement in pregnancy outcomes in Thai SLE patients was similar overtime to that in many previous reports.[5,18,20,21] However, the reason for the increased frequency of SGA and LBW was not clear, despite more frequent full-term birth infants.
This study also found that pregnancy outcomes of subsequent pregnancies in SLE patients showed a slightly decreased proportion of live births, full-term births, and SGA and LBW infants, but with slightly increased proportion of fetal loss, particularly among medical terminations. The lower proportion of SGA and LBW in the subsequent pregnancies in this study was similar to that of Wallanius et al,[22] but different from that of Korese et al,[23] who found that the fetal and maternal outcomes were almost similar between the first and subsequent pregnancies, except for the latter having slightly lower pre-term births. Reasons for the higher proportion of medical terminations in subsequent pregnancies in this study were not clear, but this might have been due to decisions made by the mothers and physicians, who were afraid of severe maternal or fetal complications if the pregnancy continued, and the patients probably had a baby already from the previous pregnancy. The proportion of cesarean section delivery among the subsequent pregnancies in this study was significantly (approximately 2 times) higher than that in the first pregnancy, which was similar to that reported by Wallenius et al.[22] This could be explained by the perception of the patients and physicians in that they were afraid of possible uterine rupture during delivery.
The PIH and eclampsia prevalence of 8.89% and 1.11%, respectively, in this study was in line with many previous reports that showed prevalence of 0–19% and 0–20% for PIH[20,23–27] and pre-eclampsia, respectively[20,23–27]. However, when looking at details, studies with a high incidence of PIH had a rather low incidence of pre-eclampsia or vise-versa; except for that reported by Wu et al,[27] and Kroese et al.[23] The reason for the discordance among these reports was unclear. It is not easy in clinical practice to differentiate between PIH and pre-eclampsia in pregnant patients with pre-existing hypertension and renal disease, as hypertension is an important clinical feature in both conditions. For example, a patient with pre-existing hypertension and some degree of proteinuria has slightly increasing proteinuria (without blood cells or cellular casts in the urine, with decreasing complement level, or increasing anti-dsDNA), and elevated blood pressure in the late course of pregnancy. In this situation, many physicians might consider PIH, while others consider pre-eclampsia. A definite diagnosis of these 2 conditions probably can be made only upon patient follow-up of the patients whether both hypertension and proteinuria are resolved or returned to baseline level prior to the development of hypertension and increasing proteinuria during the post-partum period. There were no pre-eclampsia cases in this study. As patients with increasing hypertension and slightly increasing proteinuria without active urine sediment had their blood pressure, but not the proteinuria, returned to normal or baseline during the post-partum period. These patients were considered to have PIH and not pre-eclampsia.
Similar to the differentiation between PIH and pre-eclampsia, differentiation between pre-eclampsia and active nephritis flare is another challenging issue in clinical practice. Several reviews suggest that the presence of extra-renal manifestation, past history of lupus nephritis, presence of or increasing proteinuria at the early trimester of pregnancy, presence of new hypertension onset, presence of active urinary sediments, decreasing serum complement levels, increasing anti-dsDNA levels and normal serum uric acid, favor active nephritis. However, if the aforementioned conditions occur late in the pregnancy, and the patient does not have decreasing complement or increasing anti-dsDNA levels, differential diagnosis between active nephritis and pre-eclampsia would be more difficult.[28–30] The situation would be more complicated if the patient has underlying hypertension prior to pregnancy or slight proteinuria prior to conception. Furthermore, these 2 conditions can co-exist in the same patients.[31] Some authors have suggested performing a kidney biopsy in the latter condition,[29,32] as the management of active lupus nephritis and pre-eclampsia is different. Again, sometimes the diagnosis can be made only upon delivery of the fetus when the above conditions disappear or return to normal.[3] All of the patients who had significantly increasing proteinuria in this study also had active urine sediment, and the degree of proteinuria did not return to normal or baseline at the end of the post-partum period. All of them also showed renal response to an increasing dose of corticosteroid and immunosuppressive drugs, therefore, they were more likely to have active nephritis flare rather than pre-eclampsia.
The pathogenic mechanisms of PIH and pre-eclampsia are not clear, but have been reviewed widely, and included innate immunity,[33] bioactive factors (such as inflammatory cytokines, angiogenetic factors, growth factors, etc.),[34,35] oxidative stress,[36] placental vascular maladaptation,[37] and endothelial dysfunction.[38,39] Among these, endothelial dysfunction is the most likely underlying mechanism,[39] which causes imbalance between an endothelial-derived vasodilator (such as nitric oxide and prostacyclin) and vasoconstrictors (such as endothelin-1, thromboxane A2), leading to the promotion of vasoconstriction, hypertension, and pre-eclampsia. Placenta ischemia stimulates the release of several bioactive factors and inflammatory cytokines that target the endothelial cells that lead to generalized endothelial cell dysfunction, which in turn causes vascular remodeling, increased arterial stiffness, and hypertension. Current treatment options of pre-eclampsia are limited. Only low dose aspirin has been shown as effective and is recommended by several international obstetrics and gynecologists guidelines for use in preventing pre-eclampsia in high risk patients.[40] Unfortunately, the effect of low dose aspirin on pregnancy outcomes was not determined in this study.
The effect of HCQ use on pregnancy outcomes also has been of interest in lupus pregnancy, although many previous studies could not find a significant difference in overall SLE pregnancy outcomes between HCQ users and non-users.[41–43] However, some studies showed some beneficial effects of HCQ use during pregnancy, including lower rate of fetal loss and pre-term births,[20,44] intra-uterine growth restriction (IUGR) in the fetus,[44] longer duration of pregnancy,[42] flare prevention,[43,45] and decreased PIH.[46] Although no significant difference in APOs among HCQ users and non-users was demonstrated in this study, there tended to be fewer maternal complications among HCQ users, particularly in a lower proportion of PROM, PIH and SLE flares.
Several factors have been identified in association with APOs in pregnant patients with SLE. These have included the presence of renal involvement or active nephritis,[20,24,47–53] SLE flares during pregnancy,[7,24,50,53,54] active disease prior to or during pregnancy,[20,50,54–56] hypertension,[7,24,25,54–57] presence of anti-phospholipid antibodies (APL) and/or lupus anti-coagulants,[7,20,23,24,50,53,54,56,57] cytopenia,[41,50,52,54] and hypocomplementemia.[20,25,50,54,56,58,59] This study also confirmed that renal involvement during pregnancy was associated with poor pregnancy outcomes, in both the fetus and mother. However, the presence of hypertension only associated with maternal flares.
Although APOs have been reported in several studies, only a few identified independent predicting factors for adverse fetal and maternal outcomes. In addition, the results of these predicting factors also were inconsistent. For example, Cortes-Hernandez et al[25] found that the presence of ACL and hypertension during pregnancy were independent predicting factors for poor fetal outcomes, whereas the presence of anti-β2-glycoprotein-1, hypertension at conception and hypocomplemetemia were independent predicting factors for fetal loss. Kwok et al[24] found that hypertension was an independent predicting factor for fetal loss, nephritis for SGA, low serum albumin for IUGR and SLE flares for prematurity among infants; and nephritis was an independent predicting factor for SLE flares, and hypertension and high disease activity for pre-eclampsia among mothers. Ko et al[26] found that the presence of APL antibodies was an independent predicting factor for fetal loss and pre-term births, and active disease for pre-term births. Active SLE and SLE flares were independent predicting factors for PIH and IUGR among mothers. Buyon et al[41] found that the presence of LAC, hypertension, high disease activity, maternal flares, and thrombocytopenia were predictors of APOs. Lui et al[60] found that pre-eclampsia/eclampsia and thrombocytopenia were independent predicting factors for fetal loss and SLE flares in mothers. Pre-eclampsia/eclampsia also was an independent predicting factor for pre-term birth among infants. Borella et al[56] found that hypertension was an independent predicting factor for fetal loss, miscarriage and SGA, and anti-phospholipid syndrome (APS) for prematurity in infants; whereas LAC was an independent predicting factor for pre-eclampsia, and active disease at −6 M for PROM. Kalok et al[6] found that SLE flares and active disease were predicting factors for fetal loss and pre-term birth, and also SLE flares for SGA among infants. Active SLE was an independent predicting factor for SLE flares and lupus nephritis, while SLE flares and the presence of APL antibodies were independent predicting factors for pre-eclampsia among mothers. Wu et al[59] recently found that unplanned pregnancy, hypocomplementemia and urine protein >1.0 gm/day were independent predicting factors for fetal loss. This study found that age >25 years and ever having renal involvement were independent predicting factors for fetal loss, renal involvement during pregnancy, prematurity, SGA and LBW among infants. SLE flare during pregnancy and hematologic involvement were independent predicting factors for PROM and PIH, respectively, among mothers. It was interesting that the use of prednisolone (>10 mg/day) and immunosuppressive drugs at conception was an independent protecting factor for prematurity. The presence of cutaneous vasculitis, and renal, mucocutaneous and hematologic involvement during pregnancy was an independent predicting factor for SLE flares; while the use of prednisolone (>10 mg/day) and immunosuppressive drugs at the time of conception reduced the risk of SLE flares independently. The predicting factors identified from this study were similar to many of those mentioned in the aforementioned studies. However, this study could not demonstrate that the presence of ACL/LAC was an independent factor for poor pregnancy outcomes. This might relate to the small number of patients with poor pregnancy outcome, who were among those with a positive test for these antibodies, as previously discussed. A larger study, including more patients with APL/LAC, needs to be carried out in order to verify this association in Thai patients.
The use of mSLEDAI-2K, the modified SFI and modified SLE disease activity severity score would have caused a limitation in this study. The SLE disease activity or flares would be underestimated (as the score for anti-dsDNA and complement would not be counted), making it difficult to compare this study with those that used scores from the original version. However, the mSLEDAI-2K has been shown to correlate very well (r = 0.924) with the original SLEDAI-2K.[13] In addition, use of the mSLEDAI-2K score in this study reflects real world practice, as many institutions could not perform anti-dsDNA and complements routinely. The small number of patients with positive ACL/LAC did not demonstrate the effect of these antibodies on APOs clearly. However, all of the patients in this study were taken care of by the same group of rheumatologists, who collectively made more uniformed therapeutic decisions, which should add more strength to the outcomes.
5 Conclusion
This study showed that pregnancy outcomes in Thai patients with SLE has improved over a 25-year period. However, a significant number of APOs were still observed. Renal involvement and flares during pregnancy were associated with both poor fetal and maternal outcomes. The beneficial effect of HCQ in lupus pregnancy was not demonstrated clearly, but there was a trend in favor of better pregnancy outcomes among the HCQ users. Age ≥ 25 years at conception, the presence of or ever having renal involvement during pregnancy, presence of SLE flare and hematologic involvement during pregnancy were predicting factors for poor pregnancy outcomes. Cutaneous vasculitis, and renal, hematologic and mucocutaneous involvement during pregnancy predicted SLE flare. The effect of APL/LAC on pregnancy outcomes in Thai populations needs further investigations.
Acknowledgments
The authors thank Mrs. Waraporn Sukitawut, Ms. Saowanee Pantana and Ms. Phimwalan Konkaeo for their secretarial assistance.
Author contributions
Conceptualization: Worawit Louthrenoo, Thananant Trongkamolthum, Nuntana Kasitanon, Antika Wongthanee.
Data curation: Worawit Louthrenoo, Thananant Trongkamolthum.
Formal analysis: Worawit Louthrenoo, Antika Wongthanee.
Investigation: Worawit Louthrenoo, Thananant Trongkamolthum.
Methodology: Worawit Louthrenoo, Thananant Trongkamolthum.
Supervision: Worawit Louthrenoo.
Validation: Worawit Louthrenoo, Antika Wongthanee.
Visualization: Worawit Louthrenoo, Antika Wongthanee.
Writing – original draft: Worawit Louthrenoo, Thananant Trongkamolthum.
Writing – review & editing: Worawit Louthrenoo, Thananant Trongkamolthum, Nuntana Kasitanon, Antika Wongthanee.
Abbreviations: 95% CI = 95% confidence intervals, ACL = anti-cardiolipin antibodies, ACR = American College of Rheumatology, ANA = antinuclear antibodies, Anti-dsDNA = anti-double stranded DNA antibodies, Anti-Ro = anti-Ro antibodies, Anti-Sm = anti-Smith antibodies, AOR = adjusted odds ratio, APL = anti-phospholipid antibodies, APO = adverse pregnancy outcomes, APS = anti-phospholipid syndrome, HCQ = hydroxychloroquine, HELLP syndrome = hemolysis, elevated liver enzymes, and low platelet count syndrome, IM drugs = immunosuppressive drugs, LAC = lupus coagulants, LBW = low birth weight, mSLEDAI-2K = modified Systemic Lupus Erythematosus Disease Activity Index-2000, OR = odds ratio, PGA = physician global assessment, PIH = pregnancy induced hypertension, PPH = post-partum hemorrhage, PROM = premature rupture of membrane, SDI = the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, SFI = the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE flare index, SGA = small for gestational age, SLE = systemic lupus erythematosus, VLBW = very low birth weight.
How to cite this article: Louthrenoo W, Trongkamolthum T, Kasitanon N, Wongthanee A. Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus: a STROBE-compliant study. Medicine. 2021;100:5(e24553).
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
∗ twin pregnancy.
† maternal complications (PROM + oligohydramnios = 1, PROM + post-partum hemorrhage = 1, PROM + PIH = 1, PIH + eclampsia = 1), ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, LBW = low birth weight, PIH = pregnancy induced hypertension, PPH = post-partum hemorrhage, PROM = premature rupture of membrane, SGA = small for gestational age.
∗ number of positive tests/number tested.
† excluding hydroxychloroquine, −6 M = 6 months prior to conception, ACR = American College of Rheumatology, ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, APS = anti-phospholipid syndrome, BW = birth weight, LBW = low birth weight, SDI = Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index, mSLEDAI-2K = modified systemic lupus erythematosus disease activity index – 2000, SGA = small for gestational age.
∗ number of positive tests/number tested.
† excluding hydroxychloroquine, −6 M = 6 months prior to conception, ACR = American College of Rheumatology, ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, APS = anti-phospholipid syndrome, SDI = Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index, SLEDAI-2K = systemic lupus erythematosus disease activity index – 2000.
a AOR (95% CI) = 4.15 (1.10–15.72), P = .036.
b AOR (95% CI) = 9.21 (1.03–82.51), P = .047.
c AOR (95% CI) = 3.89 (0.99–15.20), P = .051.
d AOR (95% CI) = 0.11 (0.02–0.85), P = .034.
e AOR (95% CI) = 6.0 (1.77–20.52), P = .004.
f AOR (95% CI) = 4.46 (1.44–13.78), P = .009.
g AOR (95% CI) = 10.01 (3.07–32.62), P < .001.
HCQ = hydroxychloroquine, IM drugs = immunosuppressive drugs, excluding HCQ, n = number of pregnancies with positive conditions, N1 = number of pregnancies, N2 = number of pregnancies with live births.
a AOR (95% CI) = 8.45 (1.58–45.30), P = .013.
b AOR (95% CI) = 9.24 (1.70–50.24), P = .010.
c AOR (95% CI) = 0.08 (0.01–0.68), P = .021.
d AOR (95% CI) = 33.87 (1.05–1,094.65), P = .047.
e AOR (95% CI) = 31.89 (6.66–152.69), P < .001.
f AOR (95% CI) = 9.17 (1.83–45.90), P = .007.
g AOR (95% CI) = 128.00 (4.60–3564.46), P = .004.
HCQ = hydroxychloroquine, IM drugs = immunosuppressive drugs, excluded HCQ, n = number of pregnancies with positive conditions, N1 = number of pregnancies, N2 = number of pregnancies with live birth. | Other | DrugAdministrationRoute | CC BY-NC | 33592909 | 19,221,827 | 2021-02-05 |
What was the outcome of reaction 'Foetal death'? | Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus: A STROBE-compliant study.
Studies on predicting factors for adverse pregnancy outcomes (APOs) in Thai patients with systemic lupus erythematosus (SLE) are limited. This retrospective observation study determined APOs and their predictors in Thai patients with SLE.Medical records of pregnant SLE patients in a lupus cohort, seen from January 1993 to June 2017, were reviewed.Ninety pregnancies (1 twin pregnancy) from 77 patients were identified. The mean age at conception was 26.94 ± 4.80 years. At conception, 33 patients (36.67%) had active disease, 23 (25.56%) hypertension, 20 (22.22%) renal involvement, and 6 of 43 (13.95%) positive anti-cardiolipin antibodies or lupus anti-coagulants, and 37 (41.11%) received hydroxychloroquine. Nineteen patients (21.11%) had pregnancy loss. Of 71 successful pregnancies, 28 (31.11%) infants were full-term, 42 (46.67%) pre-term and 1 (11.11%) post-term; 19 (26.39%) were small for gestational age (SGA), and 38 (52.58%) had low birth weight (LBW). Maternal complications occurred in 21 (23.33%) pregnancies [10 (11.11%) premature rupture of membrane (PROM), 8 (8.89%) pregnancy induced hypertension (PIH), 4 (4.44%) oligohydramnios, 2 (2.22%) post-partum hemorrhage, and 1 (1.11%) eclampsia]. Patients aged ≥ 25 years at pregnancy and those ever having renal involvement had predicted pregnancy loss with adjusted odds ratio (AOR) [95% CI] of 4.15 [1.10-15.72], P = .036 and 9.21 [1.03-82.51], P = .047, respectively. Renal involvement predicted prematurity (6.02 [1.77-20.52, P = .004), SGA (4.46 [1.44-13.78], P = .009), and LBW in infants (10.01 [3.07-32.62], P < .001). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception protected against prematurity (0.11 [0.02-0.85], P = .034). Flares and hematologic involvement predicted PROM (8.45 [1.58-45.30], P = .013) and PIH (9.24 [1.70-50.24], P = .010), respectively. Cutaneous vasculitis (33.87 [1.05-1,094.65], P = .047), and renal (31.89 [6.66-152.69], P < .001), mucocutaneous (9.17 [1.83-45.90], P = .007) and hematologic involvement (128.00 [4.60-3,564.46], P = .004) during pregnancy predicted flare; while prednisolone (>10 mg/day) and immunosuppressive drug use at conception reduced that risk (0.08 [0.01-0.68, P = .021).APOs remain a problem in Thai pregnant SLE patients. Renal involvement and SLE flares were associated with the risk of APOs.
1 Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ systems, characterized by remission and relapse. The disease predominantly affects women of child bearing age. Pregnancy in SLE patients is a challenging issue in clinical practice because of its association with increasing adverse outcomes in both mother and fetus.[1,2] Pregnant women with SLE have a reportedly higher rate of spontaneous abortion, fetal loss, intra-uterine growth retardation, pre-term delivery, pregnancy induced hypertension (PIH), pre-eclampsia and flares. Furthermore, pregnancy in SLE patients can cause disease exacerbation or flare, which often requires increasing doses of corticosteroids and/or immunosuppressive drugs that can have adverse effects on mother and fetus.[3,4] Thus, it is suggested that pregnancy in SLE patients should be avoided if the patients have had active severe disease within the previous 6 months, or significant heart, lung, renal and central nervous system involvement.[3,4]
With progress made in understanding the clinical course of SLE, standard instruments that determine disease activity and flares have been developed, as well as progression in medical treatment that results in improved obstetrics care of pregnant SLE patients.[3,5] Pregnancy outcomes in SLE patients have been reported widely, however, data on pregnancy outcomes from Asian countries are very limited.[6–11]
The purpose of this study was to determine pregnancy outcomes and identify independent predicting factors for adverse pregnancy outcomes (APOs) from a lupus cohort of Thai pregnant patients with SLE.
2 Patients and methods
2.1 Patients and data source
The medical records of SLE patients in a lupus cohort seen between January 1993 and June 2017 at the Division of Rheumatology, Faculty of Medicine, Chiang Mai University, Thailand were reviewed. SLE was diagnosed according to the 1997 updating the American College of Rheumatology (ACR) revised criteria for the classification of SLE.[12] Pregnant SLE patients were identified. Clinical manifestations, laboratory investigations, treatment, and SLE disease activity were recorded from 6 months prior to conception (−6 M) until 6 weeks after termination of pregnancy or delivery or the post-partum period. Pregnancy data were recorded at the time of conception or when the pregnancy was documented. The data were captured at −6 M, 3 months prior to conception (−3 M), at the time of conception, 1st trimester, 2nd trimester, 3rd trimester, and the post-partum period. If the patients had more than 1 visit during each period, the mean SLE disease activity of each period was used for statistical analysis. Laboratory investigations, including complete blood counts, urine analysis, and renal and liver functions were recorded routinely. The 24-hour urine protein creatinine ratio (24hour UPCI) [urine protein in gm/day to urine creatinine in gm/day] was determined only in cases with lupus nephritis (urine protein >0.5 gm/day). SLE patients were followed up usually in the clinic at 1 to 3 month intervals, depending on SLE disease activity or other clinical encounters. If the patients had more than 1 pregnancy, each one was considered as a separate observation and counted as an individual case.
Patients in the clinic should have been in clinical remission or have stable low disease activity (prednisolone ≤10 mg/day without immunosuppressive drugs other than anti-malarial medication) for a minimum of 12 months to allow for pregnancy to occur. Those who developed mild to moderate flares during pregnancy were administered prednisolone at a dosage of up to 0.50 mg/kg/day, and those with severe flares received >0.50 to 1.00 mg/kg/day. Anti-malarial medication was given according to clinical indications, e.g., skin rashes, oral ulcers or alopecia. Immunosuppressive drugs, particularly azathioprine and cyclosporine, were given to cases of severe flares. Cases in which the patients received methotrexate, cyclophosphamide or mycophenolate mofetil at the time of pregnancy, had these immunosuppressive drugs discontinued immediately and replaced with azathioprine or cyclosporine.
2.2 SLE disease activity and flare assessment
The modified Systemic Lupus Erythematosus Disease Activity Index-2000 (mSLEDAI-2K)[13] was used in this study to determine SLE disease activity (as anti-dsDNA and complements were not routinely available at this institution). The severity of SLE disease activity was classified according to that of Abrahamowicz et al,[14] but the mSLEDAI-2K instrument was used instead of the original SLEDAI-2K; remission [mSLEDAI-2K = 0], mild disease activity [mSLEDAI-2K = 1–5], moderate disease activity [mSLEDAI-2K = 6–10], high disease activity [mSLEDAI-2K = 11–19] and very high disease activity [mSLEDAI-2K = ≥20]). The severity of SLE flare (mild or moderate flare and severe flare) followed the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE flare index (SFI).[15] As the physician global assessment (PGA) was not recorded routinely, the SFI was modified by excluding the PGA items (mSFI). Organ damage accrual was determined using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).[16]
2.3 Pregnancy outcomes
The definition of maternal complications (premature rupture of membrane [PROM], oligohydramnios, pregnancy induced hypertension [PIH], pre-eclampsia, eclampsia, and direct and indirect maternal death), and fetal outcomes (pregnancy loss, miscarriage or spontaneous abortion, intra-uterine fetal death, medical termination of pregnancy, pre-term delivery, term delivery, post-term delivery, neonatal death, small for gestational age [SGA], and infant birth weight) followed that of standard references.[17]
2.4 Ethical statement
This study was performed in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This study was approved by the Ethic Committee of the Faculty of Medicine, Chiang Mai University (no. 215/2017).
2.5 Statistical analysis
STATA 14.2 computer software (Stata Corporation, Texas USA) was used for data processing and statistical analysis. As some patients had more than 1 pregnancy, each one was considered individually for statistical analysis. Continuous variables were presented as mean ± standard deviation (SD) or median (min-max), with categorical variables presented as percent. The Student t test and Wilcoxon rank sum test were used to determine the differences between 2 independent samples of continuous variables. One-way analysis of variance (ANOVA) and the Kruskal–Wallis test were used for more than 2 samples, with normal and non-normal distribution, respectively. The Chi-Squared test or Fisher exact test was used to determine associations among the categorical variables, where appropriate. Firth's logistic regression was used to predict the odds ratio (OR) and 95% confidence intervals (95% CI) when the outcome contained cell counts of zero. Variables with a P value <.20 from univariate analysis were entered into multiple logistic regression analysis, and reported as adjusted odds ratio (AOR) and 95% CI. A P ≤ .05 was considered as being a statistically significant difference.
3 Results
3.1 Demographics and characteristics of pregnant SLE patients
From a cohort of 1167 female SLE patients, 90 pregnancies occurred from 77 patients (1, 2, and 3 pregnancies in 66, 9 and 2 patients, respectively). Their mean age at SLE onset and age at pregnancy was 21.63 ± 5.89 years and 26.94 ± 4.80 years, respectively. Pregnancies occurred at the time of SLE diagnosis, and < 5 years and ≥ 5 years after SLE diagnosis in 7 (7.78%), 49 (54.44%) and 34 (37.78%) pregnancies, respectively. Of the 90 pregnancies, 45 (50.00%), 25 (27.78%), and 20 (22.22%) were the first, second and third or more, respectively. Their mean cumulative ACR classification criteria and SDI score were 5.49 ± 1.15 and 0.40 ± 0.72, respectively. The mean ± SD mSLEDAI-2K score at −6 M and time of conception was 1.72 ± 3.22 and 1.90 ± 3.44, respectively. Active disease at the time of conception (mSLEDAI-2K score ≥ 0) was observed in 33 of 90 pregnancies (36.67%), and all of them were unplanned. Active organ involvement at the time of conception was renal (urine protein creatinine ratio >0.5) in 20 (22.22%) pregnancies, mucocutaneous lesions in 15 (16.67%), cutaneous vasculitis in 2 (2.22%), and arthritis and hematologic abnormalities in 1 (1.11%) of each.
Co-morbidities were seen as follows: hypertension in 23 (25.56%) pregnancies, dyslipidemia in 8 (8.89%), thalassemia in 7 (7.78%), anti-phospholipid syndrome in 3 (3.33%), diabetes mellitus in 1 (1.11%), and others in 19 (21.11%) [hepatitis C virus infection, avascular necrosis of the hip, stroke and atrial secundum defect, and past history of cryptococcal meningitis, pneumocystis jirovecii pneumonia, and past treatment of pulmonary tuberculosis]. None of the patients drank alcohol or smoked.
Antinuclear antibodies (ANA) were observed in 89 pregnancies (98.89%). Anti-double stranded DNA (anti-dsDNA), anti-Smith (anti-Sm), anti-cardiolipin (ACL), lupus coagulants (LAC), and anti-Ro (anti-Ro) antibodies were observed in 50 of 85 (58.82%), 1 of 12 (8.33%), 4 of 58 (6.89%), 3 of 42 (7.14%), and 21 of 46 (45.65%) pregnancies that had been tested, respectively.
Patients in 15 of the 90 pregnancies (16.67%) had not received any specific SLE medication at the time of conception. Patients in 57 (63.33%) of the pregnancies received prednisolone at a dose of ≤10 mg/day, and in 16 (17.78%) at ≥ 10 mg/day, with the mean dosage of 10.77 ± 11.73 mg/day. Patients also received hydroxychloroquine (HCQ) in 37 (41.11%) pregnancies, cyclophosphamide in 6 (6.67%), mycophenolate mofetil in 4 (4.40%), azathioprine in 10 (11.11%), and cyclosporine in 3 (3.33%). Both cyclophosphamide and mycophenolate mofetil were switched to azathioprine or cyclosporine when the pregnancy was documented.
3.2 Overall pregnancy outcomes
Of the 90 pregnancies, 19 (21.11%) were lost (spontaneous abortion in 12 (13.33%) [7 in the 1st trimester and 5 in the 2nd], medical termination in 5 (5.56%) [1 in the 1st trimester and 4 in the 2nd], and dead fetus in the utero (1 in each 2nd and 3rd trimester). Of the 71 (78.89%) successful pregnancies, 28 (31.11%) were full-term, 42 (46.67%) pre-term (1 twin pregnancy), and 1 (1.11%) was a post-term delivery, resulting in 72 live born infants. Mode of delivery among the live births were vaginal in 52 (73.24%) and cesarean section in 19 (26.76%). The mean ± SD duration of pregnancy with live born infants was 35.76 ± 3.58 weeks. The mean ± SD weight of the 72 live born infants was 2,367.33 ± 640.30 gm (range 720–3853 gm), with normal birth weight (≥2500 gm), low birth weight (LBW) [1500–2499 gm], and very low birth weight (VLBW) [<1500 gm] in 34 (47.22%), 30 (41.67%) and 8 (11.11%) infants, respectively. SGA infants occurred in 19 live born infants (26.39%). There was 1 neonatal death (1.11%). No infants had congenital anomalies or completed heart block.
Maternal complications occurred in 21 (23.33%) pregnancies. PROM occurred in 10 (11.11%) pregnancies, PIH in 8 (8.89%), oligohydramnios in 4 (4.44%), post-partum hemorrhage in 2 (2.22%), and eclampsia in 1 (1.11%). One concomitant PROM and oligohydramnios, PROM and post-partum hemorrhage, PROM and PIH, and PIH and eclampsia occurred in each pregnancy. There were no cases of anti-partum hemorrhage, post-partum endometritis, HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), pre-eclampsia or maternal death. Thirty seven flares (41.11%) were mild to moderate and severe in 9 (24.32%) and 28 (75.68%) pregnancies, respectively.
3.3 Effect of renal involvement, hypertension, presence of anti-cardiolipin antibodies and/or lupus anti-coagulants and SLE flares on pregnancy outcomes
The effects of renal involvement, hypertension, and the presence of ACL/LAC and SLE flares on pregnancy outcomes were determined and are shown in Table 1.
Table 1 Effect of active renal involvement during pregnancy, hypertension at the time of conception, presence of anti-phospholipid antibodies and SLE flares during pregnancy on pregnancy outcomes.
Renal involvement Hypertension ACL/LAC Flares
Yes No P value Yes No P value Yes No P value Yes No P value
Successful pregnancy, n (%) 30 (75.00) 41 (82.00) .419 16 (69.57) 55 (82.09) .204 4 (66.67) 32 (86.49) .248 32 (86.49) 39 (73.58) .140
Pregnancy duration, in weeks, mean ± SD 34.34 ± 4.50 36.80 ± 2.26 .009 35.60 ± 2.47 35.81 ± 3.86 .838 38.50 ± 2.52 36.20 ± 3.45 .209 34.43 ± 3.91 36.85 ± 2.90 .004
Fetal weight, in grams, mean ± SD 2,029.52 ± 611.82 2,622.76 ± 540.06 <.001 2,147.65 ± 580.34 2,435.24 ± 647.59 .106 2,680.00 ± 557.32 2,379.94 ± 749.66 .447 2097.58 ± 615.13 2595.59 ± 575.07 .001
Fetal outcomes
Live birth, n (%) 31 (75.61)∗ 41 (82.00) .456 17 (70.83)∗ 55 (82.09) .244 4 (66.67) 32 (86.49) .248 33 (86.84)∗ 39 (73.58) .125
Term, n (%) 6 (15.00) 22 (44.00) .003 7 (30.43) 21 (31.34) .935 3 (50.00) 14 (37.84) .666 9 (24.32) 19 (35.85) .245
Pre-term, n (%) 24 (58.54)∗ 19 (38.00) .051 10 (41.67)∗ 33 (49.25) .523 1 (16.67) 17 (45.95) .177 24 (63.16)∗ 19 (35.85) .010
Post-term, n (%) 1 (2.50) 0 .444 0 1 (1.49) >.999 0 1 (2.70) >.999 0 1 (1.89) >.999
Total fetal loss, n (%) 10 (25.00) 9 (18.00) .419 7 (30.43) 12 (17.91) .204 2 (33.33) 5 (13.51) .248 5 (13.51) 14 (26.42) .140
Spontaneous abortion, n (%) 6 (15.00) 6 (12.00) .677 4 (17.39) 8 (11.94) .507 1 (16.67) 4 (10.81) .547 3 (8.11) 9 (16.98) .223
Medical termination, n (%) 2 (5.00) 3 (6.00) >.999 2 (8.70) 3 (4.48) .599 1 (16.67) 1 (2.70) .262 1 (2.70) 4 (7.55) .645
Dead fetus in the utero, n (%) 2 (5.00) 0 .195 1 (4.35) 1 (1.49) .448 0 0 1 (2.70) 1 (1.89) >.999
Neonatal death, n (%) 1 (2.50) 0 .444 1 (4.35) 0 .256 0 1 (2.70) >.999 1 (2.70) 0 .411
SGA, n (%) 13 (32.50) 6 (12.00) .018 7 (30.43) 12 (17.91) .204 1 (16.67) 12 (32.43) .649 11 (29.73) 8 (15.09) .094
LBW (< 2500 grams), n (%) 25 (60.98)∗ 13 (26.00) .001 11 (45.83)∗ 27 (40.30) .637 1 (16.67) 18 (48.65) .143 23 (60.53)∗ 15 (28.30) .002
Maternal complications†, n (%) 30 (75.00) 15 (30.00) <.001 16 (69.57) 29 (43.28) .030 2 (33.33) 18 (48.65) .669 37 (100.00) 8 (15.09) <.001
PROM, n (%) 6 (15.00) 4 (8.00) .294 1 (4.35) 9 (13.43) .232 0 4 (10.81) >.999 8 (21.62) 2 (3.77) .008
Oligohydramnios, n (%) 3 (7.50) 1 (2.00) .319 1 (4.35) 3 (4.48) >.999 0 2 (5.41) >.999 2 (5.41) 2 (3.77) >.999
PPH, n (%) 0 2 (4.00) .501 0 2 (2.99) >.999 0 1 (2.70) >.999 0 2 (3.77) .510
PIH, n (%) 5 (12.50) 3 (6.00) .282 1 (4.35) 7 (10.45) .375 0 3 (8.11) >.999 5 (13.51) 3 (5.66) .198
Eclampsia, n (%) 0 1 (2.00) >.999 0 1 (1.49) >.999 0 1 (2.70) >.999 0 1 (1.89) >.999
Flares, n (%) 27 (67.50) 10 (20.00) <.001 14 (60.87) 23 (34.33) .026 2 (33.33) 14 (37.84) >.999
Forty pregnancies were shown to have active nephritis during pregnancy. Active renal involvement occurred in 30, 30, and 26 pregnancies during the 1st, 2nd, and 3rd trimester, respectively, which was significantly higher than the 20 pregnancies seen at the time of conception (P < .001). When compared to patients without renal involvement during pregnancy, those with it had significantly shorter mean pregnancy duration (34.34 ± 4.40 weeks vs 36.80 ± 2.26 weeks, P = .003), lower fetal birth weight among live births (2029.52 ± 611.82 gm vs 2622.76 ± 540.06 gm, P < .001), and a higher proportion of LBW infants (60.98% vs 26.00%, P < .001), and SGA infants (32.50% vs 12.00%, P = .018). Although the proportion among live birth infants was not different, those with renal involvement had a significantly lower proportion of full-term infants (15.00% vs 44.00%, P = .003) and almost significantly higher proportion of pre-term infants (58.54% vs 38.00%, P = .051). There was no statistically significant difference in fetal loss among the 2 groups. The maternal complications in those with renal involvement during pregnancy were significantly higher (75.00% vs 30.00%, P < .001), which was due to a higher proportion of patients with SLE flare (67.50% vs 20.00%, P < .001). Other maternal complications, including PROM, oligohydramnios and PIH, also were higher proportionally, but they did not reach statistical significance.
Overall, there were no statistically significant differences in adverse fetal outcomes among patients with or without hypertension during pregnancy. However, pregnancy outcomes among patients with hypertension tended to have a lower proportion of live birth infants, and higher proportion of fetal loss (both spontaneous and medical terminations), SGA and LBW among full-term infants, and a lower mean fetal birth weight. Maternal complications were significantly higher in patients with hypertension (69.57% vs 43.28%, P = .030), which was due mainly to the higher proportion of those with SLE flares (60.48% vs 34.33%, P = .026). It was interesting that the proportion of PROM and PIH was lower in patients with hypertension, but with no significance.
The effect of anti-cardiolipin antibodies (ACL) and lupus anticoagulant (LAC) tests on pregnancy outcomes also was determined. Unfortunately, these 2 tests were determined in only approximately 50% of the patients. ACA and LAC were positive in a small proportion of the patients (4 of 58 or 6.89% and 3 of 42 or 7.14% of those tested, respectively). Overall, there was no statistically significant difference between either the fetal and maternal outcomes among pregnant patients with positive ACL/LAC or those without; however, those with positive ACL/LAC tended to have a lower proportion of live births and full-term birth infants, and higher proportion of fetal losses. It was interesting that the proportion of SGA, LBW, and maternal complication in the ACL/LAC positive patients also was lower, but without statistical significance. This might be due to the small number of patients in this group.
The effect of flares on pregnancy outcomes also was determined. When compared to SLE patients without flares during pregnancy, those with them had significantly shorter duration of pregnancy (34.43 ± 3.91 weeks vs 36.85 ± 2.90 weeks, P = .004), and lower mean fetal weight among live births (2097.58 ± 615.13 gm vs 2595.59 ± 575.07 gm, P = .001). Although the proportion of live birth infants and fetal loss was no different between the 2 groups, the patients with flares had a significantly higher proportion of pre-term births and LBW infants (63.16% vs 35.85%, P = .010, and 60.53% vs 28.30%, P = .002, respectively). The proportion of SGA infants also was higher, but did not reach statistical significance (29.73% vs 15.09%, P = .094). The adverse maternal outcomes were higher (100.00% vs 15.09%, P < .001), particularly of PROM (21.62% vs 3.77%, P < .008).
3.4 Effect of HCQ used on pregnancy outcomes
The effect of HCQ used during pregnancy on pregnancy outcomes was determined. Overall, there was no statistically significant difference in fetal outcomes among patients who did or did not receive HCQ during pregnancy. However, infants born to mothers who used HCQ tended to have a higher proportion of full term births (37.84% vs 26.42%, P = .249), and lower proportion of SGA (16.22% vs. 24.53%, P = .342) and LBW (36.84% vs 45.28%, P = .421). The proportion of live birth infants and fetal loss was similar between the 2 groups (78.95% vs 79.25%, P = .972, and 21.62% vs. 20.75%, P = .921, respectively). The proportion of maternal complications was lower among patients who received HCQ, and it almost reached statistical significance (37.84% vs 58.49%, P = .054). The proportion of maternal PROM, PIH and flares in the HCQ group also was lower, but did not reach statistical significance (5.41% vs 15.09%, P = .150; 5.41% vs 11.32%, P = .332, and 32.43% vs 47.17%, P = .162, respectively).
3.5 Pregnancy outcomes according to period of pregnancy, and between the first and subsequence pregnancy
The pregnancy outcomes according to the period of pregnancy (1993–2001, 2002–2009, and 2010–2017) were determined. Overall, there was no statistically significant difference in fetal or maternal outcomes between each pregnancy period. However, when comparing the pregnancy outcomes between 2010–2017, 2002–2009, and 1993–2001, fetal outcomes among pregnancies during 2010–2017 tended to have a higher proportion of live births (80.85% vs 76.00% vs 78.95%, P = .890), full-term birth infants (36.17% vs 32.00% vs 16.67%, P = .313), but with a lower proportion of pre-term birth infants (42.55% vs 44.00% vs 63.16%, P = .294), and pregnancy loss (19.15% vs 24.00% vs 22.22%, P = .884). They also had had a higher proportion of SGA and LBW (29.79% vs 16.00% vs 5.56%, P = .070, and 48.94% vs 36.00% vs 31.58%, P = .342, respectively). The proportion of maternal complications was similar (48.94% vs 48.00% vs 55.56%, P = .868); but with a tendency for decreased proportion of PROM (8.51% vs 12.00% vs 16.67%, P = .495), PIH (8.51% vs 4.00% vs 16.67%, P = .382) and SLE flares (38.30% vs 44.00% vs 44.44%, P = .851).
The pregnancy outcomes between patients with a first pregnancy and subsequent pregnancies also were compared. Similarly, there was no significant difference in fetal and maternal outcomes between the 2 groups. However, fetal outcomes in subsequent pregnancy groups tended to have a lower proportion of live births (73.91% vs 84.44%, P = .217), full-term births (24.44% vs 37.78%, P = .172), SGA (17.78% vs 24.44%, P = .438) and LBW infants (36.96% vs 46.67%, P = .348), but higher proportion of fetal loss (26.67% vs 15.56%, P = .197). Maternal complications tended to be lower (46.67% vs 53.33%, P = .527), which was due mainly to decreased proportion of SLE flares (37.78% vs 44.44%, P = .520). The rate of caesarean section was significantly higher among subsequent pregnancies (39.39% vs 15.79%, P = .025).
3.6 Predicting factors for adverse pregnancy outcomes
In order to determine independent predicting factors for APOs, the clinical characteristics that associated with adverse fetal outcomes (pregnancy loss, prematurity, SGA and LBW), and adverse maternal outcomes (PROM, PIH and flare) were compared and are shown in Tables 2 and 3, respectively.
Table 2 Comparison of clinical characteristics of adverse fetal outcomes in pregnant SLE patients.
Successful pregnancy Pregnancy loss Pre-maturity Full term + post term SGA Non-SGA LBW Normal BW
Characteristics (n = 71) (n = 19) P value (n = 42) (n = 29) P value (n = 19) (n = 52) P value (n = 37) (n = 34) P value
Age at pregnancy (in years), mean ± SD 26.30 ± 4.55 29.31 ± 5.09 .014 26.46 ± 4.73 26.07 ± 4.34 .726 25.09 ± 3.85 26.74 ± 4.73 .178 26.12 ± 4.61 26.50 ± 4.54 .726
Disease duration prior to conception (in years), mean ± SD 4.92 ± 5.01 6.99 ± 5.37 .081 4.38 ± 3.96 5.71 ± 6.21 .574 5.20 ± 4.26 4.82 ± 5.29 .451 4.54 ± 4.08 5.34 ± 5.89 .954
Co-morbidities
Hypertension, n (%) 16 (22.54) 7 (36.84) .204 9 (21.43) 7 (24.14) .788 7 (36.84) 9 (17.31) .081 10 (27.03) 6 (17.65) .345
Diabetes, n (%) 1 (1.41) 0 >.999 1 (2.38) 0 >.999 1 (5.26) 0 .268 1 (2.70) 0 >.999
Dyslipidemia, n (%) 5 (7.04) 3 (15.79) .234 3 (7.14) 2 (6.90) >.999 4 (21.05) 1 (1.92) .016 4 (10.81) 1 (2.94) .359
APS, n (%) 2 (2.82) 1 (5.26) .513 0 2 (6.90) .163 0 2 (3.85) >.999 0 2 (5.88) .226
ANA positive, n (%) 70 (98.59) 19 (100.00) >.999 41 (97.62) 29 (100.00) >.999 19 (100.00) 51 (98.08) >.999 37 (100.00) 33 (97.06) .479
Anti-dsDNA, n (%)∗ 41/67 (61.19) 9/18 (50.00) .392 26/40 (65.00) 15/27 (55.56) .436 13/19 (68.42) 28/48 (58.33) .445 25/37 (67.57) 16/30 (53.33) .234
Anti-Sm, n (%)∗ 0/11 1/1 (100.00) .083 0/7 0/4 0/2 0/9 0/6 0/5
ACL/LAC, n (%)∗ 4/36 (11.11) 2/7 (28.57) .248 1/18 (5.56) 3/18 (16.67) .603 1/13 (7.69) 3/23 (13.04) >.999 1/19 (5.26) 3/17 (17.65) .326
Anti-Ro, n (%)∗ 16/38 (42.11) 5/8 (62.50) .293 7/17 (41.18) 9/21 (42.86) .917 6/13 (46.15) 10/25 (40.00) .715 11/23 (47.83) 5/15 (33.33) .376
Anti-La, n (%)∗ 16/38 (42.11) 4/9 (44.44) .898 7/17 (41.18) 9/21 (42.86) .917 6/13 (46.15) 10/25 (40.00) .715 11/23 (47.83) 5/15 (33.33) .376
Pregnancy loss (ever), n (%) 23 (32.39) 9 (47.37) .226 12 (28.57) 11 (37.93) .407 6 (31.58) 17 (32.69) .929 11 (29.73) 12 (35.29) .617
Cumulative number of ACR criteria, mean ± SD 5.46 ± 1.11 5.58 ± 1.35 .704 5.38 ± 1.17 5.59 ± 1.02 .446 5.42 ± 1.02 5.48 ± 1.15 .842 5.35 ± 1.06 5.59 ± 1.16 .371
Disease activity (mSLEDAI-2K) at −6M, mean ± SD 1.34 ± 2.43 3.16 ± 5.05 .325 1.36 ± 2.44 1.31 ± 2.46 .960 1.42 ± 2.48 1.31 ± 2.44 .874 1.38 ± 2.53 1.29 ± 2.36 .933
Disease activity (mSLEDAI-2K) at conception, mean ± SD 1.58 ± 2.74 3.16 ± 5.22 .562 1.81 ± 2.98 1.24 ± 2.36 .385 2.16 ± 2.99 1.36 ± 2.64 .222 1.92 ± 3.22 1.20 ± 2.08 .566
Remission, n (%) 45 (63.38) 12 (63.16) .321 25 (59.52) 20 (68.97) .629 10 (52.63) 35 (67.31) .444 23 (62.16) 22 (64.71) .955
Mild, n (%) 19 (26.76) 3 (15.79) 13 (30.95) 6 (20.69) 6 (31.58) 13 (25.00) 10 (27.03) 9 (26.47)
Moderate and high, n (%) 7 (9.86) 4 (21.05) 4 (9.52) 3 (10.34) 3 (15.79) 4 (7.69) 4 (10.81) 3 (8.82)
SDI score at conception, mean ± SD 0.35 ± 0.66 0.58 ± 0.90 .400 0.36 ± 0.62 0.34 ± 0.72 .612 0.21 ± 0.42 0.40 ± 0.72 .463 0.24 ± 0.55 0.47 ± 0.75 .169
Active organ involvement during pregnancy
Renal 30 (42.25) 10 (52.63) .419 23 (54.76) 7 (24.14) .010 13 (68.42) 17 (32.69) .007 24 (64.86) 6 (17.65) <.001
Mucocutaneous 23 (32.39) 4 (21.05) .338 12 (28.57) 11 (37.93) .407 4 (21.05) 19 (36.54) .217 9 (24.32) 14 (41.18) .130
Vasculitis 2 (2.82) 1 (5.26) .513 1 (2.38) 1 (3.45) >.999 1 (5.26) 1 (1.92) .466 1 (2.70) 1 (2.94) >.999
Arthritis 2 (2.82) 0 >.999 2 (4.76) 0 .510 0 2 (3.85) >.999 1 (2.70) 1 (2.94) >.999
Hematologic 8 (11.27) 0 .125 6 (14.29) 2 (6.90) .333 4 (21.05) 4 (7.69) .197 5 (13.51) 3 (8.82) .532
Medication at conception
Prednisolone, n (%) 56 (78.87) 17 (89.47) .294 32 (76.19) 24 (82.76) .505 15 (78.95) 41 (78.85) .993 31 (83.78) 25 (73.53) .290
Dose (in mg/day), mean ± SD 9.11 ± 9.38 16.25 ± 16.58 .058 9.53 ± 9.56 8.54 ± 9.32 .412 12.50 ± 12.32 7.86 ± 7.88 .162 9.11 ± 9.39 9.10 ± 9.57 .823
Prednisolone >10 mg/day 10 (14.08) 6 (31.58) .076 6 (14.29) 4 (13.79) .953 5 (26.32) 5 (9.62) .073 6 (16.22) 4 (11.76) .590
Hydroxychloroquine, n (%) 29 (40.85) 8 (42.11) .921 15 (35.71) 14 (48.28) .290 6 (31.58) 23 (44.23) .337 13 (35.14) 16 (47.06) .307
Dose (in mg/day), mean ± SD 191.38 ± 86.67 256.25 ± 129.39 .144 183.33 ± 79.43 200.00 ± 96.08 .762 166.67 ± 51.64 197.83 ± 93.52 .533 165.38 ± 55.47 212.50 ± 102.47 .275
Immunosuppressive drug† 18 (25.35) 4 (21.05) .699 10 (23.81) 8 (27.59) .719 5 (26.32) 13 (25.00) .910 12 (32.43) 6 (17.65) .153
Mycophenolate mofetil, n (%) 4 (5.63) 0 .575 2 (4.76) 2 (6.90) >.999 1 (5.26) 3 (5.77) >.999 3 (8.11) 1 (2.94) .615
Cyclophosphamide, n (%) 3 (4.23) 3 (15.79) .106 3 (7.14) 0 .265 1 (5.26) 2 (3.85) >.999 3 (8.11) 0 .241
Azathioprine, n (%) 10 (14.08) 0 .083 5 (11.90) 5 (17.24) .525 3 (15.79) 7 (13.46) .803 6 (16.22) 4 (11.76) .590
Cyclosporine, n (%) 2 (2.82) 1 (5.26) .513 0 2 (6.90) .163 0 2 (3.85) >.999 1 (2.70) 1 (2.94) >.999
Flare during pregnancy 32 (45.07) 5 (26.32) .140 23 (54.76) 9 (31.03) .048 11 (57.89) 21 (40.38) .189 22 (59.46) 10 (29.41) .011
Table 3 Comparison of clinical characteristics of adverse maternal outcomes in pregnant SLE patients.
Premature rupture of membrane Pregnancy induced hypertension Flares
Characteristics Yes (n = 10) No (n = 80) P value Yes (n = 8) No (n = 82) P value Yes (n = 37) No (n = 53) P value
Age at pregnancy (in years), mean ± SD 28.85 ± 4.38 26.70 ± 4.82 .182 25.92 ± 3.65 27.03 ± 4.90 .535 26.89 ± 4.75 26.97 ± 4.88 .937
Disease duration prior to conception (in years), mean ± SD 3.81 ± 3.06 5.55 ± 5.31 .521 4.67 ± 6.25 5.43 ± 5.04 .257 5.67 ± 5.45 5.14 ± 4.92 .608
Co-morbidities
Hypertension, n (%) 1 (10.00) 22 (27.50) .232 1 (12.50) 22 (26.83) .375 14 (37.84) 9 (16.98) .026
Diabetes, n (%) 0 1 (1.25) >.999 0 1 (1.22) >.999 0 1 (1.89) >.999
Dyslipidemia, n (%) 0 8 (10.00) .295 0 8 (9.76) .355 3 (8.11) 5 (9.43) .828
APS, n (%) 0 3 (3.75) >.999 0 3 (3.66) >.999 2 (5.41) 1 (1.89) .566
ANA positive, n (%) 10 (100.00) 79 (98.75) >.999 7 (87.50) 82 (100.00) .089 37 (100.00) 52 (98.11) >.999
Anti-dsDNA, n (%)∗ 5/9 (55.56) 45/76 (59.21) .833 5/7 (71.43) 45/78 (57.69) .479 20/35 (57.14) 30/50 (60.00) .792
Anti-Sm, n (%)∗ 0/1 1/11 (9.09) >.999 0/1 1/11 (9.09) >.999 0/4 1/8 (12.50) >.999
ACL/LAC, n (%)∗ 0/4 6/39 (15.38) >.999 0/3 6/40 (15.00) >.999 2/16 (12.50) 4/27 (14.81) >.999
Anti-Ro, n (%)∗ 1/4 (25.00) 20/42 (47.62) .614 2/4 (50.00) 19/42 (45.24) >.999 6/15 (40.00) 15/31 (48.39) .592
Anti-La, n (%)∗ 1/4 (25.00) 19/43 (44.19) .626 2/4 (50.00) 18/43 (41.86) >.999 6/15 (40.00) 14/32 (43.75) .808
Pregnancy loss (ever), n (%) 3 (30.00) 29 (36.25) .697 2 (25.00) 30 (36.59) .513 9 (24.32) 23 (43.40) .063
Cumulative number of ACR criteria, mean ± SD 5.30 ± 1.06 5.51 ± 1.17 0.586 5.62 ± 0.52 5.48 ± 1.20 .518 5.54 ± 1.14 5.45 ± 1.17 .725
Disease activity (mSLEDAI-2K) at -6M, mean ± SD 0.40 ± 1.26 1.89 ± 3.35 .116 0.25 ± 0.71 1.86 ± 3.33 .163 1.70 ± 3.44 1.74 ± 3.09 .696
Disease activity (mSLEDAI-2K) at conception, mean ± SD 0.70 ± 1.34 2.06 ± 3.59 .400 1.00 ± 2.14 2.00 ± 3.54 .454 2.16 ± 3.92 1.74 ± 3.09 .624
Remission, n (%) 7 (70.00) 50 (62.50) 0.450 6 (75.00) 51 (62.20) .704 22 (59.46) 35 (66.04) 0.816
Mild, n (%) 3 (30.00) 19 (23.75) 1 (12.50) 21 (25.61) 10 (27.03) 12 (22.64)
Moderate and high, n (%) 0 11 (13.75) 1 (12.50) 10 (12.20) 5 (13.51) 6 (11.32)
SDI score at conception, mean ± SD 0.50 ± 0.85 0.39 ± 0.70 .728 0 ± 0 0.44 ± 0.74 .079 0.54 ± 0.80 0.30 ± 0.64 .120
Active organ involvement during pregnancy
Renal 6 (60.00) 34 (42.50) .294 5 (62.50) 35 (42.68) .282 27 (72.97) 13 (24.53) <.001
Mucocutaneous 4 (40.00) 23 (28.75) .464 4 (50.00) 23 (28.05) .234 17 (45.95) 10 (18.87) .006
Vasculitis 0 3 (3.75) >.999 0 3 (3.66) >.999 3 (8.11) 0 .066
Arthritis 0 2 (2.50) >.999 0 2 (2.44) >.999 1 (2.70) 1 (1.89) >.999
Hematologic 2 (20.00) 6 (7.50) .190 3 (37.50) 5 (6.10) .003 8 (21.62) 0 <.001
Medication at conception
Prednisolone, n (%) 8 (80.00) 65 (81.25) .924 4 (50.00) 69 (84.15) .039 29 (78.38) 44 (83.02) .580
Dose (in mg/day), mean ± SD 5.94 ± 2.65 11.36 ± 12.78 .423 19.38 ± 27.26 10.27 ± 10.41 .755 8.88 ± 7.89 12.02 ± 13.63 .958
Prednisolone >10 mg/day 0 16 (20.00) .119 1 (12.50) 15 (18.29) .683 5 (13.51) 11 (20.75) .377
Hydroxychloroquine, n (%) 2 (20.00) 35 (43.75) .150 2 (25.00) 35 (42.68) .332 12 (32.43) 25 (47.17) .162
Dose (in mg/day), mean ± SD 125.00 ± 106.07 210.00 ± 98.37 .223 150.00 ± 70.71 208.57 ± 100.36 .382 208.33 ± 129.39 204.00 ± 84.06 .797
Immunosuppressive drug† 2 (20.00) 20 (25.00) .729 0 22 (26.83) .092 7 (18.92) 15 (28.30) .308
Mycophenolate mofetil, n (%) 1 (10.00) 3 (3.75) .381 0 4 (4.88) >.999 2 (5.41) 2 (3.77) >.999
Cyclophosphamide, n (%) 0 6 (7.50) .370 0 6 (7.32) .428 1 (2.70) 5 (9.43) .208
Azathioprine, n (%) 1 (10.00) 9 (11.25) .906 0 10 (12.20) .295 4 (10.81) 6 (11.32) .940
Cyclosporine, n (%) 0 3 (3.75) >.999 0 3 (3.66) >.999 0 3 (5.66) .266
Flare during pregnancy 8 (80.00) 29 (36.25) .008 5 (62.50) 32 (39.02) .198
Factors that might be associated with adverse fetal and maternal outcomes, and those that had a statistical difference with a P value of <.2 in the univariate analysis (Tables 2 and 3) were included in the multiple logistic regression analysis (Tables 4 and 5). Independent predicting factors that increased the risk of fetal loss included age at pregnancy of ≥25 years (AOR [95% CI]) 4.15 [1.10–15.72], P = .036), and ever having renal involvement (9.21 [1.03–82.51], P = .047). Prednisolone used (>10 mg/day) at conception almost reached a predicting factor for fetal loss (3.89 [0.99–15.20], P = .051). Renal involvement during pregnancy independently predicted prematurity (6.02 [1.77–20.52], P = .004), and SGA (4.46 [1.44–13.78], P = .009) and LBW infants (10.01 [3.07–32.62], P < .001). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception independently reduced the risk of prematurity (0.11 [0.02–0.85], P = .034). SLE flares and hematologic involvement during pregnancy independently predicted PROM (8.45 [1.58–45.30], P = .013) and PIH (9.24 [1.70–50.24], P = .010), respectively. Independent predicting factors for SLE flares during pregnancy included the presence of cutaneous vasculitis (AOR [95% CI]) 33.87 [1.05–1094.65], P = .047), and renal (31.89 [6.66–152.69], P < .001), mucocutaneous (9.17 [1.83–45.90], P = .007) and hematologic involvement (128.00 [4.60–3,564.46], P = .004). Prednisolone (>10 mg/day) and immunosuppressive drugs used at conception independently reduced the risk of SLE flares during pregnancy (0.08 [0.01–0.68, P = .021).
Table 4 Univariable analysis and multiple logistic regression analysis of factors associated with adverse fetal outcomes in pregnant SLE patients.
Pregnancy loss Prematurity Small for gestational age Low birth weight
Characteristics N1 n OR (95% CI) P value N2 n OR (95% CI) P value n OR (95% CI) P value n OR (95% CI) P value
Age at pregnancy
<25 years 39 4 3.64 35 21 0.93 13 0.34 19 0.84
≥25 years 51 15 (1.01–16.37) .027a 36 21 (0.32–2.67) .886 6 (0.09–1.16) .051 18 (0.30–2.37) .718
Disease duration prior to conception
<5 years 56 8 2.87 48 28 1.11 13 0.95 26 0.78
≥5 years 34 11 (0.90–9.34) .042 23 14 (0.36–3.52) .839 6 (0.25–3.28) .929 11 (0.25–2.36) .617
Hypertension
No 67 12 2.00 55 33 0.86 12 2.79 27 1.73
Yes 23 7 (0.56–6.64) .204 16 9 (0.24–3.15) .788 7 (0.71–10.44) .081 10 (0.48–6.59) .345
Previous pregnancy
0 45 7 1.97 38 21 1.42 11 0.78 21 0.76
≥1 45 12 (0.62–6.61) .196 33 21 (0.49–4.12) .474 8 (0.23–2.56) .655 16 (0.27–2.15) .568
Pregnancy loss (ever)
No 58 10 1.88 48 30 0.65 13 0.95 26 0.78
Yes 32 9 (0.58–5.92) .226 23 12 (0.21–2.03) .408 6 (0.25–3.28) .929 11 (0.25–2.36) .617
Renal disorder (ever)
No 18 1 5.67 17 6 3.67 3 1.96 5 3.49
Yes 72 18 (0.76–249.73) .071b 54 36 (1.02–13.92) .022 16 (0.45–12.00) .330 32 (0.96–14.27) .032
SLE disease activity at conception
Remission and mild 79 15 2.44 64 38 0.91 16 2.25 33 1.25
Moderate and high 11 4 (0.46–11.06) .186 7 4 (0.14–6.76) .909 3 (0.29–14.72) .311 4 (0.19–9.22) .779
Prednisolone >10 mg/day at conception
No 74 13 2.82 61 36 1.04 14 3.36 31 1.45
Yes 16 6 (0.70–10.38) .076c 10 6 (0.22–5.55) .953 5 (0.66–16.66) .073 6 (0.31–7.68) .590
IM drugs used at conception
No 68 15 0.78 53 32 0.82 14 1.07 25 2.24
Yes 22 4 (0.17–2.93) .699 18 10 (0.24–2.83) .719 5 (0.25–3.99) .910 12 (0.65–8.33) .152
Prednisolone >10 mg/day and IM drugs used at conception
No 82 17 1.27 65 40 0.31 17 1.41 34 0.91
Yes 8 2 (0.12–7.98) .778 6 2 (0.03–2.40) .179d 2 (0.12–10.86) .704 3 (0.11–7.33) .914
HCQ used during pregnancy
No 47 11 0.75 36 23 0.67 11 0.67 21 0.60
Yes 43 8 (0.23–2.33) .577 35 19 (0.23–1.93) .410 8 (0.20–2.20) .464 16 (0.21–1.70) .287
Organ involvement during Pregnancy
Cutaneous vasculitis
No 87 18 1.92 69 41 0.68 18 2.83 36 0.92
Yes 3 1 (0.03–38.45) .598 2 1 (0.01–55.50) .789 1 (0.03–226.66) .451 1 (0.01–74.11) .952
Arthritis
No 88 19 0.71 69 40 3.64 19 0.52 36 0.92
Yes 2 0 (0.03–15.47) .829 2 2 (0.17–78.70) .410 0 (0.02–11.28) .676 1 (0.01–74.11) .952
Renal
No 50 9 1.52 41 19 3.80 6 4.46 13 8.62
Yes 40 10 (0.48–4.78) .419 30 23 (1.21–12.72) .010e 13 (1.28–16.62) .007f 24 (2.54–31.31) <.001g
Mucocutaneous
No 63 15 0.56 48 30 0.65 15 0.46 28 0.46
Yes 27 4 (0.12–2.03) .338 23 12 (0.21–2.03) .408 4 (0.10–1.76) .217 9 (0.14–1.42) .130
Hematologic
No 82 19 0.19 63 36 2.25 15 3.20 32 1.61
Yes 8 0 (0.01–3.47) .264 8 6 (0.36–24.23) .333 4 (0.52–19.11) .115 5 (0.28–11.21) .532
Flares during pregnancy
No 53 14 0.44 39 19 2.69 8 2.03 15 3.52
Yes 37 5 (0.11–1.47) .140 32 23 (0.90–8.28) .048 11 (0.62–6.84) .189 22 (1.18–10.70) .011
Table 5 Univariable analysis and multiple logistic regression analysis of factors associated with adverse maternal outcomes in pregnant SLE patients.
Premature rupture of the membrane Pregnancy induced hypertension Flares
Characteristics N n OR 95% CI P value n OR 95% CI P value n OR 95% CI P value
Age at pregnancy
<25 years 39 2 Ref. 4 Ref. 18 Ref.
≥25 years 51 8 3.44 0.62–34.83 .114 4 0.74 0.13–4.31 .690 19 0.69 (0.27–1.76) .395
Disease duration prior to conception
<5 years 56 7 Ref. 6 Ref. 22 Ref.
≥5 years 34 3 0.68 0.10–3.25 .590 2 0.52 0.05–3.17 .435 15 1.22 (0.47–3.15) .652
Hypertension
No 67 9 Ref. 7 Ref. 23 Ref.
Yes 23 1 0.29 0.01–2.36 .232 1 0.39 0.01–3.35 .375 14 2.98 (1.01–8.99) .026
Previous pregnancy
0 45 4 Ref. 4 Ref. 20 Ref.
≥1 45 6 1.58 0.34–8.16 .502 4 1.00 0.17–5.76 >.999 17 0.76 (0.30–1.91) .520
Pregnancy loss (ever)
No 58 7 Ref. 6 Ref. 28 Ref.
Yes 32 3 0.75 0.12–3.63 .697 2 0.58 0.05–3.52 .514 9 0.42 (0.14–1.15) .063
Renal disorder (ever)
No 18 1 Ref. 0 Ref. 5 Ref.
Yes 72 9 2.43 0.30–112.60 .402 8 4.88 0.27–88.50 .284 32 2.08 (0.61–8.19) .199
SLE disease activity at conception
Remission and mild 79 10 Ref. 7 Ref. 32 Ref.
Moderate and high 11 0 0.29 0.02–5.26 .401 1 1.03 0.02–9.54 .980 5 1.22 (0.27–5.27) .755
Prednisolone >10 mg/day at conception
No 74 10 Ref. 7 Ref. 32 Ref.
Yes 16 0 0.19 0.01–3.34 .254 1 0.64 0.01–5.64 .682 5 0.60 (0.15–2.11) .377
IM drugs used at conception
No 68 8 Ref. 8 Ref. 30 Ref.
Yes 22 2 0.75 0.07–4.22 .729 0 0.16 0.01–2.85 .212 7 0.59 (0.18–1.79) .308
Prednisolone >10 mg/day and IM drugs used at conception
No 82 10 Ref. 8 Ref. 36 Ref.
Yes 8 0 0.41 0.02–7.57 .546 0 0.52 0.03–9.74 .659 1 0.18 (0.00–1.55) .085c
HCQ used during pregnancy
No 47 8 Ref. 5 Ref. 20 Ref.
Yes 43 2 0.24 0.02–1.31 .062 3 0.63 0.09–3.50 .542 17 0.88 (0.35–2.22) .771
Organ involvement during pregnancy
Cutaneous vasculitis
No 87 10 Ref. 8 Ref. 34 Ref.
Yes 3 0 1.05 0.05–21.88 .973 0 1.34 0.06–28.11 .852 3 10.86 (0.54–216.71) .119d
Arthritis
No 88 10 Ref. 8 Ref. 36 Ref.
Yes 2 0 1.50 0.07–33.32 .799 0 1.89 0.08–42.79 .688 1 1.44 (0.02–115.53) .796
Renal
No 50 4 Ref. 3 Ref. 10 Ref.
Yes 40 6 2.03 0.44–10.49 .294 5 2.24 0.40–15.24 .282 27 8.31 (2.90–24.34) <.001e
Mucocutaneous
No 63 6 Ref. 4 Ref. 20 Ref.
Yes 27 4 1.65 0.31–7.69 .464 4 2.56 0.43–14.84 .196 17 3.66 (1.29–10.54) .006f
Hematologic
No 82 8 Ref. 5 Ref. 29 Ref.
Yes 8 2 3.08 0.26–21.22 .190 3 9.24 1.07–64.46 .003b 8 30.83 (1.72–553.28) .020g
Flares during pregnancy
No 53 2 Ref. 3 Ref.
Yes 37 8 7.03 1.26–70.80 .008a 5 2.60 0.46–17.73 .198
4 Discussion
Despite significant improvement in medical care for pregnant SLE patients, their APOs are still a significant issue.[5,18] Fetal loss (both spontaneous abortion and intra-uterine death), pre-term birth, intra-uterine growth retardation, SGA and LBW in the fetus, and PIH, pre-eclampsia/eclampsia and flares in the mother are among the major APOs of concern. Reports on SLE patients with APOs varied greatly among studies. This could be explain partly by the difference in time period of the study and ethnicity and socioeconomic status of the patients, as well as SLE disease activity prior to and at the time of conception, organ involvement at conception, rate and organ of flares, and prevalence of ACL/LAC or anti-phospholipid syndrome in the population studied.[1,3,19]
Progressive improvement in pregnancy outcomes over a 25-year period was observed in this study. The proportion of successful pregnancies tended to improve with an increased proportion of full-term births and decreased proportion of pre-term infants. An increased proportion of infants with SGA and LBW had slightly decreased mean fetal birth weight; although all of these changes did not reach statistical significance. The improvement in pregnancy outcomes in Thai SLE patients was similar overtime to that in many previous reports.[5,18,20,21] However, the reason for the increased frequency of SGA and LBW was not clear, despite more frequent full-term birth infants.
This study also found that pregnancy outcomes of subsequent pregnancies in SLE patients showed a slightly decreased proportion of live births, full-term births, and SGA and LBW infants, but with slightly increased proportion of fetal loss, particularly among medical terminations. The lower proportion of SGA and LBW in the subsequent pregnancies in this study was similar to that of Wallanius et al,[22] but different from that of Korese et al,[23] who found that the fetal and maternal outcomes were almost similar between the first and subsequent pregnancies, except for the latter having slightly lower pre-term births. Reasons for the higher proportion of medical terminations in subsequent pregnancies in this study were not clear, but this might have been due to decisions made by the mothers and physicians, who were afraid of severe maternal or fetal complications if the pregnancy continued, and the patients probably had a baby already from the previous pregnancy. The proportion of cesarean section delivery among the subsequent pregnancies in this study was significantly (approximately 2 times) higher than that in the first pregnancy, which was similar to that reported by Wallenius et al.[22] This could be explained by the perception of the patients and physicians in that they were afraid of possible uterine rupture during delivery.
The PIH and eclampsia prevalence of 8.89% and 1.11%, respectively, in this study was in line with many previous reports that showed prevalence of 0–19% and 0–20% for PIH[20,23–27] and pre-eclampsia, respectively[20,23–27]. However, when looking at details, studies with a high incidence of PIH had a rather low incidence of pre-eclampsia or vise-versa; except for that reported by Wu et al,[27] and Kroese et al.[23] The reason for the discordance among these reports was unclear. It is not easy in clinical practice to differentiate between PIH and pre-eclampsia in pregnant patients with pre-existing hypertension and renal disease, as hypertension is an important clinical feature in both conditions. For example, a patient with pre-existing hypertension and some degree of proteinuria has slightly increasing proteinuria (without blood cells or cellular casts in the urine, with decreasing complement level, or increasing anti-dsDNA), and elevated blood pressure in the late course of pregnancy. In this situation, many physicians might consider PIH, while others consider pre-eclampsia. A definite diagnosis of these 2 conditions probably can be made only upon patient follow-up of the patients whether both hypertension and proteinuria are resolved or returned to baseline level prior to the development of hypertension and increasing proteinuria during the post-partum period. There were no pre-eclampsia cases in this study. As patients with increasing hypertension and slightly increasing proteinuria without active urine sediment had their blood pressure, but not the proteinuria, returned to normal or baseline during the post-partum period. These patients were considered to have PIH and not pre-eclampsia.
Similar to the differentiation between PIH and pre-eclampsia, differentiation between pre-eclampsia and active nephritis flare is another challenging issue in clinical practice. Several reviews suggest that the presence of extra-renal manifestation, past history of lupus nephritis, presence of or increasing proteinuria at the early trimester of pregnancy, presence of new hypertension onset, presence of active urinary sediments, decreasing serum complement levels, increasing anti-dsDNA levels and normal serum uric acid, favor active nephritis. However, if the aforementioned conditions occur late in the pregnancy, and the patient does not have decreasing complement or increasing anti-dsDNA levels, differential diagnosis between active nephritis and pre-eclampsia would be more difficult.[28–30] The situation would be more complicated if the patient has underlying hypertension prior to pregnancy or slight proteinuria prior to conception. Furthermore, these 2 conditions can co-exist in the same patients.[31] Some authors have suggested performing a kidney biopsy in the latter condition,[29,32] as the management of active lupus nephritis and pre-eclampsia is different. Again, sometimes the diagnosis can be made only upon delivery of the fetus when the above conditions disappear or return to normal.[3] All of the patients who had significantly increasing proteinuria in this study also had active urine sediment, and the degree of proteinuria did not return to normal or baseline at the end of the post-partum period. All of them also showed renal response to an increasing dose of corticosteroid and immunosuppressive drugs, therefore, they were more likely to have active nephritis flare rather than pre-eclampsia.
The pathogenic mechanisms of PIH and pre-eclampsia are not clear, but have been reviewed widely, and included innate immunity,[33] bioactive factors (such as inflammatory cytokines, angiogenetic factors, growth factors, etc.),[34,35] oxidative stress,[36] placental vascular maladaptation,[37] and endothelial dysfunction.[38,39] Among these, endothelial dysfunction is the most likely underlying mechanism,[39] which causes imbalance between an endothelial-derived vasodilator (such as nitric oxide and prostacyclin) and vasoconstrictors (such as endothelin-1, thromboxane A2), leading to the promotion of vasoconstriction, hypertension, and pre-eclampsia. Placenta ischemia stimulates the release of several bioactive factors and inflammatory cytokines that target the endothelial cells that lead to generalized endothelial cell dysfunction, which in turn causes vascular remodeling, increased arterial stiffness, and hypertension. Current treatment options of pre-eclampsia are limited. Only low dose aspirin has been shown as effective and is recommended by several international obstetrics and gynecologists guidelines for use in preventing pre-eclampsia in high risk patients.[40] Unfortunately, the effect of low dose aspirin on pregnancy outcomes was not determined in this study.
The effect of HCQ use on pregnancy outcomes also has been of interest in lupus pregnancy, although many previous studies could not find a significant difference in overall SLE pregnancy outcomes between HCQ users and non-users.[41–43] However, some studies showed some beneficial effects of HCQ use during pregnancy, including lower rate of fetal loss and pre-term births,[20,44] intra-uterine growth restriction (IUGR) in the fetus,[44] longer duration of pregnancy,[42] flare prevention,[43,45] and decreased PIH.[46] Although no significant difference in APOs among HCQ users and non-users was demonstrated in this study, there tended to be fewer maternal complications among HCQ users, particularly in a lower proportion of PROM, PIH and SLE flares.
Several factors have been identified in association with APOs in pregnant patients with SLE. These have included the presence of renal involvement or active nephritis,[20,24,47–53] SLE flares during pregnancy,[7,24,50,53,54] active disease prior to or during pregnancy,[20,50,54–56] hypertension,[7,24,25,54–57] presence of anti-phospholipid antibodies (APL) and/or lupus anti-coagulants,[7,20,23,24,50,53,54,56,57] cytopenia,[41,50,52,54] and hypocomplementemia.[20,25,50,54,56,58,59] This study also confirmed that renal involvement during pregnancy was associated with poor pregnancy outcomes, in both the fetus and mother. However, the presence of hypertension only associated with maternal flares.
Although APOs have been reported in several studies, only a few identified independent predicting factors for adverse fetal and maternal outcomes. In addition, the results of these predicting factors also were inconsistent. For example, Cortes-Hernandez et al[25] found that the presence of ACL and hypertension during pregnancy were independent predicting factors for poor fetal outcomes, whereas the presence of anti-β2-glycoprotein-1, hypertension at conception and hypocomplemetemia were independent predicting factors for fetal loss. Kwok et al[24] found that hypertension was an independent predicting factor for fetal loss, nephritis for SGA, low serum albumin for IUGR and SLE flares for prematurity among infants; and nephritis was an independent predicting factor for SLE flares, and hypertension and high disease activity for pre-eclampsia among mothers. Ko et al[26] found that the presence of APL antibodies was an independent predicting factor for fetal loss and pre-term births, and active disease for pre-term births. Active SLE and SLE flares were independent predicting factors for PIH and IUGR among mothers. Buyon et al[41] found that the presence of LAC, hypertension, high disease activity, maternal flares, and thrombocytopenia were predictors of APOs. Lui et al[60] found that pre-eclampsia/eclampsia and thrombocytopenia were independent predicting factors for fetal loss and SLE flares in mothers. Pre-eclampsia/eclampsia also was an independent predicting factor for pre-term birth among infants. Borella et al[56] found that hypertension was an independent predicting factor for fetal loss, miscarriage and SGA, and anti-phospholipid syndrome (APS) for prematurity in infants; whereas LAC was an independent predicting factor for pre-eclampsia, and active disease at −6 M for PROM. Kalok et al[6] found that SLE flares and active disease were predicting factors for fetal loss and pre-term birth, and also SLE flares for SGA among infants. Active SLE was an independent predicting factor for SLE flares and lupus nephritis, while SLE flares and the presence of APL antibodies were independent predicting factors for pre-eclampsia among mothers. Wu et al[59] recently found that unplanned pregnancy, hypocomplementemia and urine protein >1.0 gm/day were independent predicting factors for fetal loss. This study found that age >25 years and ever having renal involvement were independent predicting factors for fetal loss, renal involvement during pregnancy, prematurity, SGA and LBW among infants. SLE flare during pregnancy and hematologic involvement were independent predicting factors for PROM and PIH, respectively, among mothers. It was interesting that the use of prednisolone (>10 mg/day) and immunosuppressive drugs at conception was an independent protecting factor for prematurity. The presence of cutaneous vasculitis, and renal, mucocutaneous and hematologic involvement during pregnancy was an independent predicting factor for SLE flares; while the use of prednisolone (>10 mg/day) and immunosuppressive drugs at the time of conception reduced the risk of SLE flares independently. The predicting factors identified from this study were similar to many of those mentioned in the aforementioned studies. However, this study could not demonstrate that the presence of ACL/LAC was an independent factor for poor pregnancy outcomes. This might relate to the small number of patients with poor pregnancy outcome, who were among those with a positive test for these antibodies, as previously discussed. A larger study, including more patients with APL/LAC, needs to be carried out in order to verify this association in Thai patients.
The use of mSLEDAI-2K, the modified SFI and modified SLE disease activity severity score would have caused a limitation in this study. The SLE disease activity or flares would be underestimated (as the score for anti-dsDNA and complement would not be counted), making it difficult to compare this study with those that used scores from the original version. However, the mSLEDAI-2K has been shown to correlate very well (r = 0.924) with the original SLEDAI-2K.[13] In addition, use of the mSLEDAI-2K score in this study reflects real world practice, as many institutions could not perform anti-dsDNA and complements routinely. The small number of patients with positive ACL/LAC did not demonstrate the effect of these antibodies on APOs clearly. However, all of the patients in this study were taken care of by the same group of rheumatologists, who collectively made more uniformed therapeutic decisions, which should add more strength to the outcomes.
5 Conclusion
This study showed that pregnancy outcomes in Thai patients with SLE has improved over a 25-year period. However, a significant number of APOs were still observed. Renal involvement and flares during pregnancy were associated with both poor fetal and maternal outcomes. The beneficial effect of HCQ in lupus pregnancy was not demonstrated clearly, but there was a trend in favor of better pregnancy outcomes among the HCQ users. Age ≥ 25 years at conception, the presence of or ever having renal involvement during pregnancy, presence of SLE flare and hematologic involvement during pregnancy were predicting factors for poor pregnancy outcomes. Cutaneous vasculitis, and renal, hematologic and mucocutaneous involvement during pregnancy predicted SLE flare. The effect of APL/LAC on pregnancy outcomes in Thai populations needs further investigations.
Acknowledgments
The authors thank Mrs. Waraporn Sukitawut, Ms. Saowanee Pantana and Ms. Phimwalan Konkaeo for their secretarial assistance.
Author contributions
Conceptualization: Worawit Louthrenoo, Thananant Trongkamolthum, Nuntana Kasitanon, Antika Wongthanee.
Data curation: Worawit Louthrenoo, Thananant Trongkamolthum.
Formal analysis: Worawit Louthrenoo, Antika Wongthanee.
Investigation: Worawit Louthrenoo, Thananant Trongkamolthum.
Methodology: Worawit Louthrenoo, Thananant Trongkamolthum.
Supervision: Worawit Louthrenoo.
Validation: Worawit Louthrenoo, Antika Wongthanee.
Visualization: Worawit Louthrenoo, Antika Wongthanee.
Writing – original draft: Worawit Louthrenoo, Thananant Trongkamolthum.
Writing – review & editing: Worawit Louthrenoo, Thananant Trongkamolthum, Nuntana Kasitanon, Antika Wongthanee.
Abbreviations: 95% CI = 95% confidence intervals, ACL = anti-cardiolipin antibodies, ACR = American College of Rheumatology, ANA = antinuclear antibodies, Anti-dsDNA = anti-double stranded DNA antibodies, Anti-Ro = anti-Ro antibodies, Anti-Sm = anti-Smith antibodies, AOR = adjusted odds ratio, APL = anti-phospholipid antibodies, APO = adverse pregnancy outcomes, APS = anti-phospholipid syndrome, HCQ = hydroxychloroquine, HELLP syndrome = hemolysis, elevated liver enzymes, and low platelet count syndrome, IM drugs = immunosuppressive drugs, LAC = lupus coagulants, LBW = low birth weight, mSLEDAI-2K = modified Systemic Lupus Erythematosus Disease Activity Index-2000, OR = odds ratio, PGA = physician global assessment, PIH = pregnancy induced hypertension, PPH = post-partum hemorrhage, PROM = premature rupture of membrane, SDI = the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, SFI = the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLE flare index, SGA = small for gestational age, SLE = systemic lupus erythematosus, VLBW = very low birth weight.
How to cite this article: Louthrenoo W, Trongkamolthum T, Kasitanon N, Wongthanee A. Predicting factors of adverse pregnancy outcomes in Thai patients with systemic lupus erythematosus: a STROBE-compliant study. Medicine. 2021;100:5(e24553).
The authors have no conflicts of interests to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
∗ twin pregnancy.
† maternal complications (PROM + oligohydramnios = 1, PROM + post-partum hemorrhage = 1, PROM + PIH = 1, PIH + eclampsia = 1), ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, LBW = low birth weight, PIH = pregnancy induced hypertension, PPH = post-partum hemorrhage, PROM = premature rupture of membrane, SGA = small for gestational age.
∗ number of positive tests/number tested.
† excluding hydroxychloroquine, −6 M = 6 months prior to conception, ACR = American College of Rheumatology, ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, APS = anti-phospholipid syndrome, BW = birth weight, LBW = low birth weight, SDI = Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index, mSLEDAI-2K = modified systemic lupus erythematosus disease activity index – 2000, SGA = small for gestational age.
∗ number of positive tests/number tested.
† excluding hydroxychloroquine, −6 M = 6 months prior to conception, ACR = American College of Rheumatology, ACL/LAC = anti-cardiolipin antibodies/lupus anti-coagulants, APS = anti-phospholipid syndrome, SDI = Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index, SLEDAI-2K = systemic lupus erythematosus disease activity index – 2000.
a AOR (95% CI) = 4.15 (1.10–15.72), P = .036.
b AOR (95% CI) = 9.21 (1.03–82.51), P = .047.
c AOR (95% CI) = 3.89 (0.99–15.20), P = .051.
d AOR (95% CI) = 0.11 (0.02–0.85), P = .034.
e AOR (95% CI) = 6.0 (1.77–20.52), P = .004.
f AOR (95% CI) = 4.46 (1.44–13.78), P = .009.
g AOR (95% CI) = 10.01 (3.07–32.62), P < .001.
HCQ = hydroxychloroquine, IM drugs = immunosuppressive drugs, excluding HCQ, n = number of pregnancies with positive conditions, N1 = number of pregnancies, N2 = number of pregnancies with live births.
a AOR (95% CI) = 8.45 (1.58–45.30), P = .013.
b AOR (95% CI) = 9.24 (1.70–50.24), P = .010.
c AOR (95% CI) = 0.08 (0.01–0.68), P = .021.
d AOR (95% CI) = 33.87 (1.05–1,094.65), P = .047.
e AOR (95% CI) = 31.89 (6.66–152.69), P < .001.
f AOR (95% CI) = 9.17 (1.83–45.90), P = .007.
g AOR (95% CI) = 128.00 (4.60–3564.46), P = .004.
HCQ = hydroxychloroquine, IM drugs = immunosuppressive drugs, excluded HCQ, n = number of pregnancies with positive conditions, N1 = number of pregnancies, N2 = number of pregnancies with live birth. | Fatal | ReactionOutcome | CC BY-NC | 33592909 | 19,221,827 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytomegalovirus infection'. | Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.
Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.
However, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.
The current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.
Subjects and Methods
Patient Characteristics
We retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.
TM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.
Haploidentical Donor Selection
We performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.
Cord Blood
Cord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.
Preparative Regimen
Pre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.
Post-Transplantation Immunosuppression
GVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.
Supportive Care
Patients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.
Patients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.
Patient Evaluations
All patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.
Definition of Engraftment
Myeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.
Statistical Methods
OS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.
Results
Patient Characteristics
Patient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.
Table 1. Patient Characteristics.
Patient characteristics
Total number
73
Median age at transplantation age (years, range)
7 (3 to 14)
Risk assessment
Low
2 (3%)
Intermediate
42 (57%)
High
29 (40%)
Sex
Female
27 (37%)
Male
46 (63%)
HLA matching
5/10
45 (62%)
6/10
15 (21%)
7/10
9 (12%)
8/10
4 (5%)
Donor
Brother
14 (19%)
Sister
10 (15%)
Father
39 (54%)
Mother
8 (11%)
Other relative
1 (1%)
ABO blood type
Matched
23 (32%)
Mismatched
50 (68%)
Stem cell source
PBSC alone
57 (78%)
PBSC + BM
16 (22%)
Stem cell engraftment
Haplo
43 (59%)
Cord blood
30 (41%)
MNC dose (108/kg) (median, range)
20 (10.60 to 32.20)
CD34+ dose (106/kg) (median, range)
15.45 (2.60 to 62.00)
Cell engraftment (median, range)
Days to neutrophil engraftment
22 (15 to 48)
Days to platelet engraftment
20 (8 to 99)
Primary or secondary graft failure
0
BM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.
No primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.
GVHD and Other Complications
As shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).
Table 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.
Complications Number of patients
Acute GVHD
38 (52%)
I to II
20 (27%)
III to IV
18 (25%)
Use of steroids
18
Chronic GVHD
27 (37%)
Mild
26 (36%)
Severe
1 (1%)
Infections
CMV-DNAemia
35 (48%)
CMV diseases
5 (7%)
EBV-DNAemia
19 (26%)
PTLD
5 (7%)
Herpetic zoster reactivation
6 (10%)
HHV6
1 (1%)
BKV related hemorrhagic cystitis
7 (9%)
Sepsis
3 (5%)
Tuberculosis
1 (1%)
Streptococcus meningitis
1 (1%)
Invasive fungal infection
7 (10%)
Other complications
Poor graft function (PGF)
6 (8%)
Primary PGF
4 (5%)
Secondary PGF
2 (3%)
SOS/VOD
6 (8%)
Mucositis
18 (25%)
Refractory autoimmune haemolytic anemia
1 (1%)
Cause of death
Chronic GVHD
1
Secondary PGF
1
Refractory autoimmune hemolytic anaemia
1
Follow up time (median, range)
811 (370 to 1433)
GVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Cytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.
Overall Survival and Transfusion-Free Survival
The estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).
Fig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).
Cord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity
Patient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).
Fig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.
Fig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).
Discussion
This is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.
Most TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.
As a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.
A relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.
The percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.
Compared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.
Of the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.
Another limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.
In conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.
Supplemental Material
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Acknowledgments
We thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.
Ethical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.
Statement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.
Statement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).
ORCID iDs: Xiaoling Zhang
https://orcid.org/0000-0002-1940-0202
Uet Yu
https://orcid.org/0000-0003-4391-3398
Supplemental Material: Supplemental material for this article is available online. | AZATHIOPRINE, BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, HYDROXYUREA, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS, THIOTEPA | DrugsGivenReaction | CC BY-NC | 33593080 | 20,336,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Epstein-Barr virus infection'. | Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.
Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.
However, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.
The current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.
Subjects and Methods
Patient Characteristics
We retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.
TM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.
Haploidentical Donor Selection
We performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.
Cord Blood
Cord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.
Preparative Regimen
Pre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.
Post-Transplantation Immunosuppression
GVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.
Supportive Care
Patients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.
Patients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.
Patient Evaluations
All patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.
Definition of Engraftment
Myeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.
Statistical Methods
OS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.
Results
Patient Characteristics
Patient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.
Table 1. Patient Characteristics.
Patient characteristics
Total number
73
Median age at transplantation age (years, range)
7 (3 to 14)
Risk assessment
Low
2 (3%)
Intermediate
42 (57%)
High
29 (40%)
Sex
Female
27 (37%)
Male
46 (63%)
HLA matching
5/10
45 (62%)
6/10
15 (21%)
7/10
9 (12%)
8/10
4 (5%)
Donor
Brother
14 (19%)
Sister
10 (15%)
Father
39 (54%)
Mother
8 (11%)
Other relative
1 (1%)
ABO blood type
Matched
23 (32%)
Mismatched
50 (68%)
Stem cell source
PBSC alone
57 (78%)
PBSC + BM
16 (22%)
Stem cell engraftment
Haplo
43 (59%)
Cord blood
30 (41%)
MNC dose (108/kg) (median, range)
20 (10.60 to 32.20)
CD34+ dose (106/kg) (median, range)
15.45 (2.60 to 62.00)
Cell engraftment (median, range)
Days to neutrophil engraftment
22 (15 to 48)
Days to platelet engraftment
20 (8 to 99)
Primary or secondary graft failure
0
BM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.
No primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.
GVHD and Other Complications
As shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).
Table 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.
Complications Number of patients
Acute GVHD
38 (52%)
I to II
20 (27%)
III to IV
18 (25%)
Use of steroids
18
Chronic GVHD
27 (37%)
Mild
26 (36%)
Severe
1 (1%)
Infections
CMV-DNAemia
35 (48%)
CMV diseases
5 (7%)
EBV-DNAemia
19 (26%)
PTLD
5 (7%)
Herpetic zoster reactivation
6 (10%)
HHV6
1 (1%)
BKV related hemorrhagic cystitis
7 (9%)
Sepsis
3 (5%)
Tuberculosis
1 (1%)
Streptococcus meningitis
1 (1%)
Invasive fungal infection
7 (10%)
Other complications
Poor graft function (PGF)
6 (8%)
Primary PGF
4 (5%)
Secondary PGF
2 (3%)
SOS/VOD
6 (8%)
Mucositis
18 (25%)
Refractory autoimmune haemolytic anemia
1 (1%)
Cause of death
Chronic GVHD
1
Secondary PGF
1
Refractory autoimmune hemolytic anaemia
1
Follow up time (median, range)
811 (370 to 1433)
GVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Cytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.
Overall Survival and Transfusion-Free Survival
The estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).
Fig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).
Cord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity
Patient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).
Fig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.
Fig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).
Discussion
This is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.
Most TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.
As a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.
A relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.
The percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.
Compared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.
Of the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.
Another limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.
In conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.
Supplemental Material
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Acknowledgments
We thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.
Ethical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.
Statement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.
Statement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).
ORCID iDs: Xiaoling Zhang
https://orcid.org/0000-0002-1940-0202
Uet Yu
https://orcid.org/0000-0003-4391-3398
Supplemental Material: Supplemental material for this article is available online. | AZATHIOPRINE, BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, HYDROXYUREA, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS, THIOTEPA | DrugsGivenReaction | CC BY-NC | 33593080 | 20,336,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fungal infection'. | Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.
Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.
However, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.
The current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.
Subjects and Methods
Patient Characteristics
We retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.
TM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.
Haploidentical Donor Selection
We performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.
Cord Blood
Cord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.
Preparative Regimen
Pre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.
Post-Transplantation Immunosuppression
GVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.
Supportive Care
Patients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.
Patients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.
Patient Evaluations
All patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.
Definition of Engraftment
Myeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.
Statistical Methods
OS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.
Results
Patient Characteristics
Patient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.
Table 1. Patient Characteristics.
Patient characteristics
Total number
73
Median age at transplantation age (years, range)
7 (3 to 14)
Risk assessment
Low
2 (3%)
Intermediate
42 (57%)
High
29 (40%)
Sex
Female
27 (37%)
Male
46 (63%)
HLA matching
5/10
45 (62%)
6/10
15 (21%)
7/10
9 (12%)
8/10
4 (5%)
Donor
Brother
14 (19%)
Sister
10 (15%)
Father
39 (54%)
Mother
8 (11%)
Other relative
1 (1%)
ABO blood type
Matched
23 (32%)
Mismatched
50 (68%)
Stem cell source
PBSC alone
57 (78%)
PBSC + BM
16 (22%)
Stem cell engraftment
Haplo
43 (59%)
Cord blood
30 (41%)
MNC dose (108/kg) (median, range)
20 (10.60 to 32.20)
CD34+ dose (106/kg) (median, range)
15.45 (2.60 to 62.00)
Cell engraftment (median, range)
Days to neutrophil engraftment
22 (15 to 48)
Days to platelet engraftment
20 (8 to 99)
Primary or secondary graft failure
0
BM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.
No primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.
GVHD and Other Complications
As shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).
Table 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.
Complications Number of patients
Acute GVHD
38 (52%)
I to II
20 (27%)
III to IV
18 (25%)
Use of steroids
18
Chronic GVHD
27 (37%)
Mild
26 (36%)
Severe
1 (1%)
Infections
CMV-DNAemia
35 (48%)
CMV diseases
5 (7%)
EBV-DNAemia
19 (26%)
PTLD
5 (7%)
Herpetic zoster reactivation
6 (10%)
HHV6
1 (1%)
BKV related hemorrhagic cystitis
7 (9%)
Sepsis
3 (5%)
Tuberculosis
1 (1%)
Streptococcus meningitis
1 (1%)
Invasive fungal infection
7 (10%)
Other complications
Poor graft function (PGF)
6 (8%)
Primary PGF
4 (5%)
Secondary PGF
2 (3%)
SOS/VOD
6 (8%)
Mucositis
18 (25%)
Refractory autoimmune haemolytic anemia
1 (1%)
Cause of death
Chronic GVHD
1
Secondary PGF
1
Refractory autoimmune hemolytic anaemia
1
Follow up time (median, range)
811 (370 to 1433)
GVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Cytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.
Overall Survival and Transfusion-Free Survival
The estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).
Fig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).
Cord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity
Patient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).
Fig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.
Fig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).
Discussion
This is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.
Most TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.
As a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.
A relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.
The percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.
Compared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.
Of the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.
Another limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.
In conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.
Supplemental Material
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Acknowledgments
We thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.
Ethical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.
Statement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.
Statement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).
ORCID iDs: Xiaoling Zhang
https://orcid.org/0000-0002-1940-0202
Uet Yu
https://orcid.org/0000-0003-4391-3398
Supplemental Material: Supplemental material for this article is available online. | AZATHIOPRINE, BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, HYDROXYUREA, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS, THIOTEPA | DrugsGivenReaction | CC BY-NC | 33593080 | 20,336,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Herpes zoster reactivation'. | Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.
Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.
However, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.
The current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.
Subjects and Methods
Patient Characteristics
We retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.
TM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.
Haploidentical Donor Selection
We performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.
Cord Blood
Cord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.
Preparative Regimen
Pre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.
Post-Transplantation Immunosuppression
GVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.
Supportive Care
Patients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.
Patients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.
Patient Evaluations
All patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.
Definition of Engraftment
Myeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.
Statistical Methods
OS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.
Results
Patient Characteristics
Patient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.
Table 1. Patient Characteristics.
Patient characteristics
Total number
73
Median age at transplantation age (years, range)
7 (3 to 14)
Risk assessment
Low
2 (3%)
Intermediate
42 (57%)
High
29 (40%)
Sex
Female
27 (37%)
Male
46 (63%)
HLA matching
5/10
45 (62%)
6/10
15 (21%)
7/10
9 (12%)
8/10
4 (5%)
Donor
Brother
14 (19%)
Sister
10 (15%)
Father
39 (54%)
Mother
8 (11%)
Other relative
1 (1%)
ABO blood type
Matched
23 (32%)
Mismatched
50 (68%)
Stem cell source
PBSC alone
57 (78%)
PBSC + BM
16 (22%)
Stem cell engraftment
Haplo
43 (59%)
Cord blood
30 (41%)
MNC dose (108/kg) (median, range)
20 (10.60 to 32.20)
CD34+ dose (106/kg) (median, range)
15.45 (2.60 to 62.00)
Cell engraftment (median, range)
Days to neutrophil engraftment
22 (15 to 48)
Days to platelet engraftment
20 (8 to 99)
Primary or secondary graft failure
0
BM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.
No primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.
GVHD and Other Complications
As shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).
Table 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.
Complications Number of patients
Acute GVHD
38 (52%)
I to II
20 (27%)
III to IV
18 (25%)
Use of steroids
18
Chronic GVHD
27 (37%)
Mild
26 (36%)
Severe
1 (1%)
Infections
CMV-DNAemia
35 (48%)
CMV diseases
5 (7%)
EBV-DNAemia
19 (26%)
PTLD
5 (7%)
Herpetic zoster reactivation
6 (10%)
HHV6
1 (1%)
BKV related hemorrhagic cystitis
7 (9%)
Sepsis
3 (5%)
Tuberculosis
1 (1%)
Streptococcus meningitis
1 (1%)
Invasive fungal infection
7 (10%)
Other complications
Poor graft function (PGF)
6 (8%)
Primary PGF
4 (5%)
Secondary PGF
2 (3%)
SOS/VOD
6 (8%)
Mucositis
18 (25%)
Refractory autoimmune haemolytic anemia
1 (1%)
Cause of death
Chronic GVHD
1
Secondary PGF
1
Refractory autoimmune hemolytic anaemia
1
Follow up time (median, range)
811 (370 to 1433)
GVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Cytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.
Overall Survival and Transfusion-Free Survival
The estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).
Fig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).
Cord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity
Patient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).
Fig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.
Fig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).
Discussion
This is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.
Most TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.
As a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.
A relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.
The percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.
Compared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.
Of the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.
Another limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.
In conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.
Supplemental Material
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Acknowledgments
We thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.
Ethical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.
Statement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.
Statement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).
ORCID iDs: Xiaoling Zhang
https://orcid.org/0000-0002-1940-0202
Uet Yu
https://orcid.org/0000-0003-4391-3398
Supplemental Material: Supplemental material for this article is available online. | AZATHIOPRINE, BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, HYDROXYUREA, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS, THIOTEPA | DrugsGivenReaction | CC BY-NC | 33593080 | 20,336,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Human herpesvirus 6 infection'. | Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.
Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.
However, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.
The current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.
Subjects and Methods
Patient Characteristics
We retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.
TM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.
Haploidentical Donor Selection
We performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.
Cord Blood
Cord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.
Preparative Regimen
Pre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.
Post-Transplantation Immunosuppression
GVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.
Supportive Care
Patients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.
Patients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.
Patient Evaluations
All patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.
Definition of Engraftment
Myeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.
Statistical Methods
OS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.
Results
Patient Characteristics
Patient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.
Table 1. Patient Characteristics.
Patient characteristics
Total number
73
Median age at transplantation age (years, range)
7 (3 to 14)
Risk assessment
Low
2 (3%)
Intermediate
42 (57%)
High
29 (40%)
Sex
Female
27 (37%)
Male
46 (63%)
HLA matching
5/10
45 (62%)
6/10
15 (21%)
7/10
9 (12%)
8/10
4 (5%)
Donor
Brother
14 (19%)
Sister
10 (15%)
Father
39 (54%)
Mother
8 (11%)
Other relative
1 (1%)
ABO blood type
Matched
23 (32%)
Mismatched
50 (68%)
Stem cell source
PBSC alone
57 (78%)
PBSC + BM
16 (22%)
Stem cell engraftment
Haplo
43 (59%)
Cord blood
30 (41%)
MNC dose (108/kg) (median, range)
20 (10.60 to 32.20)
CD34+ dose (106/kg) (median, range)
15.45 (2.60 to 62.00)
Cell engraftment (median, range)
Days to neutrophil engraftment
22 (15 to 48)
Days to platelet engraftment
20 (8 to 99)
Primary or secondary graft failure
0
BM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.
No primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.
GVHD and Other Complications
As shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).
Table 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.
Complications Number of patients
Acute GVHD
38 (52%)
I to II
20 (27%)
III to IV
18 (25%)
Use of steroids
18
Chronic GVHD
27 (37%)
Mild
26 (36%)
Severe
1 (1%)
Infections
CMV-DNAemia
35 (48%)
CMV diseases
5 (7%)
EBV-DNAemia
19 (26%)
PTLD
5 (7%)
Herpetic zoster reactivation
6 (10%)
HHV6
1 (1%)
BKV related hemorrhagic cystitis
7 (9%)
Sepsis
3 (5%)
Tuberculosis
1 (1%)
Streptococcus meningitis
1 (1%)
Invasive fungal infection
7 (10%)
Other complications
Poor graft function (PGF)
6 (8%)
Primary PGF
4 (5%)
Secondary PGF
2 (3%)
SOS/VOD
6 (8%)
Mucositis
18 (25%)
Refractory autoimmune haemolytic anemia
1 (1%)
Cause of death
Chronic GVHD
1
Secondary PGF
1
Refractory autoimmune hemolytic anaemia
1
Follow up time (median, range)
811 (370 to 1433)
GVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Cytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.
Overall Survival and Transfusion-Free Survival
The estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).
Fig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).
Cord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity
Patient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).
Fig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.
Fig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).
Discussion
This is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.
Most TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.
As a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.
A relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.
The percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.
Compared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.
Of the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.
Another limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.
In conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.
Supplemental Material
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Acknowledgments
We thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.
Ethical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.
Statement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.
Statement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).
ORCID iDs: Xiaoling Zhang
https://orcid.org/0000-0002-1940-0202
Uet Yu
https://orcid.org/0000-0003-4391-3398
Supplemental Material: Supplemental material for this article is available online. | AZATHIOPRINE, BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, HYDROXYUREA, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS, THIOTEPA | DrugsGivenReaction | CC BY-NC | 33593080 | 20,336,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Meningitis streptococcal'. | Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.
Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.
However, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.
The current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.
Subjects and Methods
Patient Characteristics
We retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.
TM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.
Haploidentical Donor Selection
We performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.
Cord Blood
Cord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.
Preparative Regimen
Pre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.
Post-Transplantation Immunosuppression
GVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.
Supportive Care
Patients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.
Patients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.
Patient Evaluations
All patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.
Definition of Engraftment
Myeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.
Statistical Methods
OS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.
Results
Patient Characteristics
Patient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.
Table 1. Patient Characteristics.
Patient characteristics
Total number
73
Median age at transplantation age (years, range)
7 (3 to 14)
Risk assessment
Low
2 (3%)
Intermediate
42 (57%)
High
29 (40%)
Sex
Female
27 (37%)
Male
46 (63%)
HLA matching
5/10
45 (62%)
6/10
15 (21%)
7/10
9 (12%)
8/10
4 (5%)
Donor
Brother
14 (19%)
Sister
10 (15%)
Father
39 (54%)
Mother
8 (11%)
Other relative
1 (1%)
ABO blood type
Matched
23 (32%)
Mismatched
50 (68%)
Stem cell source
PBSC alone
57 (78%)
PBSC + BM
16 (22%)
Stem cell engraftment
Haplo
43 (59%)
Cord blood
30 (41%)
MNC dose (108/kg) (median, range)
20 (10.60 to 32.20)
CD34+ dose (106/kg) (median, range)
15.45 (2.60 to 62.00)
Cell engraftment (median, range)
Days to neutrophil engraftment
22 (15 to 48)
Days to platelet engraftment
20 (8 to 99)
Primary or secondary graft failure
0
BM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.
No primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.
GVHD and Other Complications
As shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).
Table 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.
Complications Number of patients
Acute GVHD
38 (52%)
I to II
20 (27%)
III to IV
18 (25%)
Use of steroids
18
Chronic GVHD
27 (37%)
Mild
26 (36%)
Severe
1 (1%)
Infections
CMV-DNAemia
35 (48%)
CMV diseases
5 (7%)
EBV-DNAemia
19 (26%)
PTLD
5 (7%)
Herpetic zoster reactivation
6 (10%)
HHV6
1 (1%)
BKV related hemorrhagic cystitis
7 (9%)
Sepsis
3 (5%)
Tuberculosis
1 (1%)
Streptococcus meningitis
1 (1%)
Invasive fungal infection
7 (10%)
Other complications
Poor graft function (PGF)
6 (8%)
Primary PGF
4 (5%)
Secondary PGF
2 (3%)
SOS/VOD
6 (8%)
Mucositis
18 (25%)
Refractory autoimmune haemolytic anemia
1 (1%)
Cause of death
Chronic GVHD
1
Secondary PGF
1
Refractory autoimmune hemolytic anaemia
1
Follow up time (median, range)
811 (370 to 1433)
GVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Cytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.
Overall Survival and Transfusion-Free Survival
The estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).
Fig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).
Cord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity
Patient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).
Fig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.
Fig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).
Discussion
This is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.
Most TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.
As a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.
A relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.
The percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.
Compared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.
Of the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.
Another limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.
In conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.
Supplemental Material
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Acknowledgments
We thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.
Ethical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.
Statement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.
Statement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).
ORCID iDs: Xiaoling Zhang
https://orcid.org/0000-0002-1940-0202
Uet Yu
https://orcid.org/0000-0003-4391-3398
Supplemental Material: Supplemental material for this article is available online. | AZATHIOPRINE, BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, HYDROXYUREA, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS, THIOTEPA | DrugsGivenReaction | CC BY-NC | 33593080 | 20,336,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mucosal inflammation'. | Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.
Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.
However, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.
The current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.
Subjects and Methods
Patient Characteristics
We retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.
TM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.
Haploidentical Donor Selection
We performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.
Cord Blood
Cord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.
Preparative Regimen
Pre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.
Post-Transplantation Immunosuppression
GVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.
Supportive Care
Patients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.
Patients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.
Patient Evaluations
All patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.
Definition of Engraftment
Myeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.
Statistical Methods
OS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.
Results
Patient Characteristics
Patient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.
Table 1. Patient Characteristics.
Patient characteristics
Total number
73
Median age at transplantation age (years, range)
7 (3 to 14)
Risk assessment
Low
2 (3%)
Intermediate
42 (57%)
High
29 (40%)
Sex
Female
27 (37%)
Male
46 (63%)
HLA matching
5/10
45 (62%)
6/10
15 (21%)
7/10
9 (12%)
8/10
4 (5%)
Donor
Brother
14 (19%)
Sister
10 (15%)
Father
39 (54%)
Mother
8 (11%)
Other relative
1 (1%)
ABO blood type
Matched
23 (32%)
Mismatched
50 (68%)
Stem cell source
PBSC alone
57 (78%)
PBSC + BM
16 (22%)
Stem cell engraftment
Haplo
43 (59%)
Cord blood
30 (41%)
MNC dose (108/kg) (median, range)
20 (10.60 to 32.20)
CD34+ dose (106/kg) (median, range)
15.45 (2.60 to 62.00)
Cell engraftment (median, range)
Days to neutrophil engraftment
22 (15 to 48)
Days to platelet engraftment
20 (8 to 99)
Primary or secondary graft failure
0
BM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.
No primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.
GVHD and Other Complications
As shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).
Table 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.
Complications Number of patients
Acute GVHD
38 (52%)
I to II
20 (27%)
III to IV
18 (25%)
Use of steroids
18
Chronic GVHD
27 (37%)
Mild
26 (36%)
Severe
1 (1%)
Infections
CMV-DNAemia
35 (48%)
CMV diseases
5 (7%)
EBV-DNAemia
19 (26%)
PTLD
5 (7%)
Herpetic zoster reactivation
6 (10%)
HHV6
1 (1%)
BKV related hemorrhagic cystitis
7 (9%)
Sepsis
3 (5%)
Tuberculosis
1 (1%)
Streptococcus meningitis
1 (1%)
Invasive fungal infection
7 (10%)
Other complications
Poor graft function (PGF)
6 (8%)
Primary PGF
4 (5%)
Secondary PGF
2 (3%)
SOS/VOD
6 (8%)
Mucositis
18 (25%)
Refractory autoimmune haemolytic anemia
1 (1%)
Cause of death
Chronic GVHD
1
Secondary PGF
1
Refractory autoimmune hemolytic anaemia
1
Follow up time (median, range)
811 (370 to 1433)
GVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Cytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.
Overall Survival and Transfusion-Free Survival
The estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).
Fig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).
Cord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity
Patient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).
Fig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.
Fig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).
Discussion
This is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.
Most TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.
As a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.
A relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.
The percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.
Compared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.
Of the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.
Another limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.
In conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.
Supplemental Material
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Acknowledgments
We thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.
Ethical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.
Statement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.
Statement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).
ORCID iDs: Xiaoling Zhang
https://orcid.org/0000-0002-1940-0202
Uet Yu
https://orcid.org/0000-0003-4391-3398
Supplemental Material: Supplemental material for this article is available online. | AZATHIOPRINE, BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, HYDROXYUREA, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS, THIOTEPA | DrugsGivenReaction | CC BY-NC | 33593080 | 20,336,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Post transplant lymphoproliferative disorder'. | Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.
Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.
However, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.
The current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.
Subjects and Methods
Patient Characteristics
We retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.
TM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.
Haploidentical Donor Selection
We performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.
Cord Blood
Cord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.
Preparative Regimen
Pre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.
Post-Transplantation Immunosuppression
GVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.
Supportive Care
Patients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.
Patients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.
Patient Evaluations
All patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.
Definition of Engraftment
Myeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.
Statistical Methods
OS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.
Results
Patient Characteristics
Patient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.
Table 1. Patient Characteristics.
Patient characteristics
Total number
73
Median age at transplantation age (years, range)
7 (3 to 14)
Risk assessment
Low
2 (3%)
Intermediate
42 (57%)
High
29 (40%)
Sex
Female
27 (37%)
Male
46 (63%)
HLA matching
5/10
45 (62%)
6/10
15 (21%)
7/10
9 (12%)
8/10
4 (5%)
Donor
Brother
14 (19%)
Sister
10 (15%)
Father
39 (54%)
Mother
8 (11%)
Other relative
1 (1%)
ABO blood type
Matched
23 (32%)
Mismatched
50 (68%)
Stem cell source
PBSC alone
57 (78%)
PBSC + BM
16 (22%)
Stem cell engraftment
Haplo
43 (59%)
Cord blood
30 (41%)
MNC dose (108/kg) (median, range)
20 (10.60 to 32.20)
CD34+ dose (106/kg) (median, range)
15.45 (2.60 to 62.00)
Cell engraftment (median, range)
Days to neutrophil engraftment
22 (15 to 48)
Days to platelet engraftment
20 (8 to 99)
Primary or secondary graft failure
0
BM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.
No primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.
GVHD and Other Complications
As shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).
Table 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.
Complications Number of patients
Acute GVHD
38 (52%)
I to II
20 (27%)
III to IV
18 (25%)
Use of steroids
18
Chronic GVHD
27 (37%)
Mild
26 (36%)
Severe
1 (1%)
Infections
CMV-DNAemia
35 (48%)
CMV diseases
5 (7%)
EBV-DNAemia
19 (26%)
PTLD
5 (7%)
Herpetic zoster reactivation
6 (10%)
HHV6
1 (1%)
BKV related hemorrhagic cystitis
7 (9%)
Sepsis
3 (5%)
Tuberculosis
1 (1%)
Streptococcus meningitis
1 (1%)
Invasive fungal infection
7 (10%)
Other complications
Poor graft function (PGF)
6 (8%)
Primary PGF
4 (5%)
Secondary PGF
2 (3%)
SOS/VOD
6 (8%)
Mucositis
18 (25%)
Refractory autoimmune haemolytic anemia
1 (1%)
Cause of death
Chronic GVHD
1
Secondary PGF
1
Refractory autoimmune hemolytic anaemia
1
Follow up time (median, range)
811 (370 to 1433)
GVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Cytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.
Overall Survival and Transfusion-Free Survival
The estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).
Fig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).
Cord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity
Patient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).
Fig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.
Fig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).
Discussion
This is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.
Most TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.
As a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.
A relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.
The percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.
Compared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.
Of the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.
Another limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.
In conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.
Supplemental Material
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Acknowledgments
We thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.
Ethical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.
Statement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.
Statement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).
ORCID iDs: Xiaoling Zhang
https://orcid.org/0000-0002-1940-0202
Uet Yu
https://orcid.org/0000-0003-4391-3398
Supplemental Material: Supplemental material for this article is available online. | AZATHIOPRINE, BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, HYDROXYUREA, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS, THIOTEPA | DrugsGivenReaction | CC BY-NC | 33593080 | 20,336,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sepsis'. | Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.
Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.
However, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.
The current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.
Subjects and Methods
Patient Characteristics
We retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.
TM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.
Haploidentical Donor Selection
We performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.
Cord Blood
Cord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.
Preparative Regimen
Pre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.
Post-Transplantation Immunosuppression
GVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.
Supportive Care
Patients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.
Patients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.
Patient Evaluations
All patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.
Definition of Engraftment
Myeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.
Statistical Methods
OS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.
Results
Patient Characteristics
Patient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.
Table 1. Patient Characteristics.
Patient characteristics
Total number
73
Median age at transplantation age (years, range)
7 (3 to 14)
Risk assessment
Low
2 (3%)
Intermediate
42 (57%)
High
29 (40%)
Sex
Female
27 (37%)
Male
46 (63%)
HLA matching
5/10
45 (62%)
6/10
15 (21%)
7/10
9 (12%)
8/10
4 (5%)
Donor
Brother
14 (19%)
Sister
10 (15%)
Father
39 (54%)
Mother
8 (11%)
Other relative
1 (1%)
ABO blood type
Matched
23 (32%)
Mismatched
50 (68%)
Stem cell source
PBSC alone
57 (78%)
PBSC + BM
16 (22%)
Stem cell engraftment
Haplo
43 (59%)
Cord blood
30 (41%)
MNC dose (108/kg) (median, range)
20 (10.60 to 32.20)
CD34+ dose (106/kg) (median, range)
15.45 (2.60 to 62.00)
Cell engraftment (median, range)
Days to neutrophil engraftment
22 (15 to 48)
Days to platelet engraftment
20 (8 to 99)
Primary or secondary graft failure
0
BM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.
No primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.
GVHD and Other Complications
As shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).
Table 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.
Complications Number of patients
Acute GVHD
38 (52%)
I to II
20 (27%)
III to IV
18 (25%)
Use of steroids
18
Chronic GVHD
27 (37%)
Mild
26 (36%)
Severe
1 (1%)
Infections
CMV-DNAemia
35 (48%)
CMV diseases
5 (7%)
EBV-DNAemia
19 (26%)
PTLD
5 (7%)
Herpetic zoster reactivation
6 (10%)
HHV6
1 (1%)
BKV related hemorrhagic cystitis
7 (9%)
Sepsis
3 (5%)
Tuberculosis
1 (1%)
Streptococcus meningitis
1 (1%)
Invasive fungal infection
7 (10%)
Other complications
Poor graft function (PGF)
6 (8%)
Primary PGF
4 (5%)
Secondary PGF
2 (3%)
SOS/VOD
6 (8%)
Mucositis
18 (25%)
Refractory autoimmune haemolytic anemia
1 (1%)
Cause of death
Chronic GVHD
1
Secondary PGF
1
Refractory autoimmune hemolytic anaemia
1
Follow up time (median, range)
811 (370 to 1433)
GVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Cytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.
Overall Survival and Transfusion-Free Survival
The estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).
Fig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).
Cord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity
Patient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).
Fig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.
Fig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).
Discussion
This is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.
Most TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.
As a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.
A relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.
The percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.
Compared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.
Of the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.
Another limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.
In conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.
Supplemental Material
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Acknowledgments
We thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.
Ethical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.
Statement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.
Statement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).
ORCID iDs: Xiaoling Zhang
https://orcid.org/0000-0002-1940-0202
Uet Yu
https://orcid.org/0000-0003-4391-3398
Supplemental Material: Supplemental material for this article is available online. | AZATHIOPRINE, BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, HYDROXYUREA, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS, THIOTEPA | DrugsGivenReaction | CC BY-NC | 33593080 | 20,336,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tuberculosis'. | Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.
Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.
However, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.
The current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.
Subjects and Methods
Patient Characteristics
We retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.
TM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.
Haploidentical Donor Selection
We performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.
Cord Blood
Cord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.
Preparative Regimen
Pre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.
Post-Transplantation Immunosuppression
GVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.
Supportive Care
Patients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.
Patients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.
Patient Evaluations
All patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.
Definition of Engraftment
Myeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.
Statistical Methods
OS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.
Results
Patient Characteristics
Patient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.
Table 1. Patient Characteristics.
Patient characteristics
Total number
73
Median age at transplantation age (years, range)
7 (3 to 14)
Risk assessment
Low
2 (3%)
Intermediate
42 (57%)
High
29 (40%)
Sex
Female
27 (37%)
Male
46 (63%)
HLA matching
5/10
45 (62%)
6/10
15 (21%)
7/10
9 (12%)
8/10
4 (5%)
Donor
Brother
14 (19%)
Sister
10 (15%)
Father
39 (54%)
Mother
8 (11%)
Other relative
1 (1%)
ABO blood type
Matched
23 (32%)
Mismatched
50 (68%)
Stem cell source
PBSC alone
57 (78%)
PBSC + BM
16 (22%)
Stem cell engraftment
Haplo
43 (59%)
Cord blood
30 (41%)
MNC dose (108/kg) (median, range)
20 (10.60 to 32.20)
CD34+ dose (106/kg) (median, range)
15.45 (2.60 to 62.00)
Cell engraftment (median, range)
Days to neutrophil engraftment
22 (15 to 48)
Days to platelet engraftment
20 (8 to 99)
Primary or secondary graft failure
0
BM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.
No primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.
GVHD and Other Complications
As shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).
Table 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.
Complications Number of patients
Acute GVHD
38 (52%)
I to II
20 (27%)
III to IV
18 (25%)
Use of steroids
18
Chronic GVHD
27 (37%)
Mild
26 (36%)
Severe
1 (1%)
Infections
CMV-DNAemia
35 (48%)
CMV diseases
5 (7%)
EBV-DNAemia
19 (26%)
PTLD
5 (7%)
Herpetic zoster reactivation
6 (10%)
HHV6
1 (1%)
BKV related hemorrhagic cystitis
7 (9%)
Sepsis
3 (5%)
Tuberculosis
1 (1%)
Streptococcus meningitis
1 (1%)
Invasive fungal infection
7 (10%)
Other complications
Poor graft function (PGF)
6 (8%)
Primary PGF
4 (5%)
Secondary PGF
2 (3%)
SOS/VOD
6 (8%)
Mucositis
18 (25%)
Refractory autoimmune haemolytic anemia
1 (1%)
Cause of death
Chronic GVHD
1
Secondary PGF
1
Refractory autoimmune hemolytic anaemia
1
Follow up time (median, range)
811 (370 to 1433)
GVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Cytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.
Overall Survival and Transfusion-Free Survival
The estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).
Fig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).
Cord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity
Patient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).
Fig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.
Fig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).
Discussion
This is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.
Most TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.
As a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.
A relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.
The percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.
Compared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.
Of the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.
Another limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.
In conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.
Supplemental Material
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Acknowledgments
We thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.
Ethical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.
Statement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.
Statement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).
ORCID iDs: Xiaoling Zhang
https://orcid.org/0000-0002-1940-0202
Uet Yu
https://orcid.org/0000-0003-4391-3398
Supplemental Material: Supplemental material for this article is available online. | AZATHIOPRINE, BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, HYDROXYUREA, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS, THIOTEPA | DrugsGivenReaction | CC BY-NC | 33593080 | 20,336,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Venoocclusive disease'. | Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.
Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.
However, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.
The current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.
Subjects and Methods
Patient Characteristics
We retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.
TM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.
Haploidentical Donor Selection
We performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.
Cord Blood
Cord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.
Preparative Regimen
Pre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.
Post-Transplantation Immunosuppression
GVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.
Supportive Care
Patients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.
Patients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.
Patient Evaluations
All patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.
Definition of Engraftment
Myeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.
Statistical Methods
OS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.
Results
Patient Characteristics
Patient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.
Table 1. Patient Characteristics.
Patient characteristics
Total number
73
Median age at transplantation age (years, range)
7 (3 to 14)
Risk assessment
Low
2 (3%)
Intermediate
42 (57%)
High
29 (40%)
Sex
Female
27 (37%)
Male
46 (63%)
HLA matching
5/10
45 (62%)
6/10
15 (21%)
7/10
9 (12%)
8/10
4 (5%)
Donor
Brother
14 (19%)
Sister
10 (15%)
Father
39 (54%)
Mother
8 (11%)
Other relative
1 (1%)
ABO blood type
Matched
23 (32%)
Mismatched
50 (68%)
Stem cell source
PBSC alone
57 (78%)
PBSC + BM
16 (22%)
Stem cell engraftment
Haplo
43 (59%)
Cord blood
30 (41%)
MNC dose (108/kg) (median, range)
20 (10.60 to 32.20)
CD34+ dose (106/kg) (median, range)
15.45 (2.60 to 62.00)
Cell engraftment (median, range)
Days to neutrophil engraftment
22 (15 to 48)
Days to platelet engraftment
20 (8 to 99)
Primary or secondary graft failure
0
BM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.
No primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.
GVHD and Other Complications
As shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).
Table 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.
Complications Number of patients
Acute GVHD
38 (52%)
I to II
20 (27%)
III to IV
18 (25%)
Use of steroids
18
Chronic GVHD
27 (37%)
Mild
26 (36%)
Severe
1 (1%)
Infections
CMV-DNAemia
35 (48%)
CMV diseases
5 (7%)
EBV-DNAemia
19 (26%)
PTLD
5 (7%)
Herpetic zoster reactivation
6 (10%)
HHV6
1 (1%)
BKV related hemorrhagic cystitis
7 (9%)
Sepsis
3 (5%)
Tuberculosis
1 (1%)
Streptococcus meningitis
1 (1%)
Invasive fungal infection
7 (10%)
Other complications
Poor graft function (PGF)
6 (8%)
Primary PGF
4 (5%)
Secondary PGF
2 (3%)
SOS/VOD
6 (8%)
Mucositis
18 (25%)
Refractory autoimmune haemolytic anemia
1 (1%)
Cause of death
Chronic GVHD
1
Secondary PGF
1
Refractory autoimmune hemolytic anaemia
1
Follow up time (median, range)
811 (370 to 1433)
GVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Cytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.
Overall Survival and Transfusion-Free Survival
The estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).
Fig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).
Cord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity
Patient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).
Fig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.
Fig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).
Discussion
This is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.
Most TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.
As a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.
A relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.
The percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.
Compared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.
Of the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.
Another limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.
In conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.
Supplemental Material
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Acknowledgments
We thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.
Ethical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.
Statement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.
Statement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).
ORCID iDs: Xiaoling Zhang
https://orcid.org/0000-0002-1940-0202
Uet Yu
https://orcid.org/0000-0003-4391-3398
Supplemental Material: Supplemental material for this article is available online. | AZATHIOPRINE, BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, HYDROXYUREA, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS, THIOTEPA | DrugsGivenReaction | CC BY-NC | 33593080 | 20,336,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Venoocclusive liver disease'. | Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.
Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.
However, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.
The current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.
Subjects and Methods
Patient Characteristics
We retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.
TM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.
Haploidentical Donor Selection
We performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.
Cord Blood
Cord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.
Preparative Regimen
Pre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.
Post-Transplantation Immunosuppression
GVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.
Supportive Care
Patients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.
Patients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.
Patient Evaluations
All patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.
Definition of Engraftment
Myeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.
Statistical Methods
OS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.
Results
Patient Characteristics
Patient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.
Table 1. Patient Characteristics.
Patient characteristics
Total number
73
Median age at transplantation age (years, range)
7 (3 to 14)
Risk assessment
Low
2 (3%)
Intermediate
42 (57%)
High
29 (40%)
Sex
Female
27 (37%)
Male
46 (63%)
HLA matching
5/10
45 (62%)
6/10
15 (21%)
7/10
9 (12%)
8/10
4 (5%)
Donor
Brother
14 (19%)
Sister
10 (15%)
Father
39 (54%)
Mother
8 (11%)
Other relative
1 (1%)
ABO blood type
Matched
23 (32%)
Mismatched
50 (68%)
Stem cell source
PBSC alone
57 (78%)
PBSC + BM
16 (22%)
Stem cell engraftment
Haplo
43 (59%)
Cord blood
30 (41%)
MNC dose (108/kg) (median, range)
20 (10.60 to 32.20)
CD34+ dose (106/kg) (median, range)
15.45 (2.60 to 62.00)
Cell engraftment (median, range)
Days to neutrophil engraftment
22 (15 to 48)
Days to platelet engraftment
20 (8 to 99)
Primary or secondary graft failure
0
BM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.
No primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.
GVHD and Other Complications
As shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).
Table 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.
Complications Number of patients
Acute GVHD
38 (52%)
I to II
20 (27%)
III to IV
18 (25%)
Use of steroids
18
Chronic GVHD
27 (37%)
Mild
26 (36%)
Severe
1 (1%)
Infections
CMV-DNAemia
35 (48%)
CMV diseases
5 (7%)
EBV-DNAemia
19 (26%)
PTLD
5 (7%)
Herpetic zoster reactivation
6 (10%)
HHV6
1 (1%)
BKV related hemorrhagic cystitis
7 (9%)
Sepsis
3 (5%)
Tuberculosis
1 (1%)
Streptococcus meningitis
1 (1%)
Invasive fungal infection
7 (10%)
Other complications
Poor graft function (PGF)
6 (8%)
Primary PGF
4 (5%)
Secondary PGF
2 (3%)
SOS/VOD
6 (8%)
Mucositis
18 (25%)
Refractory autoimmune haemolytic anemia
1 (1%)
Cause of death
Chronic GVHD
1
Secondary PGF
1
Refractory autoimmune hemolytic anaemia
1
Follow up time (median, range)
811 (370 to 1433)
GVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Cytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.
Overall Survival and Transfusion-Free Survival
The estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).
Fig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).
Cord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity
Patient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).
Fig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.
Fig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).
Discussion
This is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.
Most TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.
As a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.
A relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.
The percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.
Compared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.
Of the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.
Another limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.
In conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.
Supplemental Material
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Acknowledgments
We thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.
Ethical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.
Statement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.
Statement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).
ORCID iDs: Xiaoling Zhang
https://orcid.org/0000-0002-1940-0202
Uet Yu
https://orcid.org/0000-0003-4391-3398
Supplemental Material: Supplemental material for this article is available online. | AZATHIOPRINE, BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, HYDROXYUREA, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS, THIOTEPA | DrugsGivenReaction | CC BY-NC | 33593080 | 20,336,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Viral haemorrhagic cystitis'. | Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major.
Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.
Introduction
Allogeneic hematopoietic stem cell transplantation (HSCT) provides a potential cure for thalassemia major (TM) patients and it is a more cost-effective treatment than lifelong blood transfusion and chelation therapy1–3. Transplants from matched related or unrelated donors are the primary treatment choice for individuals with TM and other hemoglobinopathies4. However, less than a quarter of patients in China find fully human leukocyte antigen (HLA)-matched unrelated donors5,6. In the last decade, haploidentical stem cell transplantation (haplo-SCT) has multiplied the options for alternative donors. Recent advances in haplo-SCT programs, particularly the optimization of graft selection strategies, the development of in vivo and ex vivo T cell depletion methodologies, and the application of post-transplantation cyclophosphamide (PTCY), have greatly improved overall survival (OS) and event-free survival (EFS), as well as reducing comorbidities7–12.
However, studies investigating the application of haplo-SCT for TM patients are limited. Early attempts have shown an association between TM recipients, a high graft failure rate, and a low probability of survival10,13,14. Nevertheless, recent haplo-SCT protocols have exhibited competitive or even superior outcomes, with OS and EFS values up to 96% of those using matched related and unrelated donors11,15–18. However, the outcomes of TM patients that received haplo-SCT vary between different transplant programs. Therefore, additional evidence to confirm long-term safety and efficacy is required.
The current study developed a co-transplantation program for pediatric TM patients consisting of haplo-SCT and a single-dose transfusion of unrelated cord blood on day 6 after transplantation (haplo-cord program)19,20. As the haplo-cord program has shown promising results in other diseases20–24, we hypothesized that this program would have encouraging outcomes and long-term advantages in patients with TM.
Subjects and Methods
Patient Characteristics
We retrospectively reviewed the data for 73 TM patients (27 females and 46 males) aged 3 to 14 years (median age 7 years) who had undergone haplo-cord transplantation at Shenzhen Children’s Hospital, China between September 2016 and June 2019. One patient who received haplo-cord transplantation as a second transplantation was excluded before the analysis. All patients, donors, and their respective patient and donor parents were given written consents for the collection, analysis, and publication of their outcome data. This study was approved by the Institutional Review Board of Shenzhen Children’s Hospital in accordance with the Helsinki Declaration.
TM patients in this study included those diagnosed with β-TM or compound β-TM and α-thalassemia based on a genetic examination. Risk assessments were performed based on age at transplantation, serum ferritin level, and hepatosplenomegaly severity25. Patients were classified into low-risk, intermediate-risk, and high-risk groups before transplantation.
Haploidentical Donor Selection
We performed high-resolution HLA typing for HLA-A, B, C, DR, and DQ for all donors and recipients. Selection of non-maternal haploidentical donors was favored unless a maternal donor was the only available option. Granulocyte colony-stimulating factor (GCSF, 10 μg/kg/d) was administered to donors once a day for 4 consecutive days for stem cell mobilization before transplantation. Peripheral blood stem cells (PBSCs) with or without bone marrow (BM) were collected from haploidentical donors. Apheresis started on day 5 after mobilization and, if required, continued on the next day until at least 20 × 107 nucleated cells/L/body weight of the recipient were collected.
Cord Blood
Cord blood was selected based on both HLA typing and total nucleated cell counting as shown in previous published strategies by others19,26. Grafts that matched for at least four of six HLA loci (HLA-A, HLA-B, and HLA-DR) and contained a minimum nucleated cell count of 1 × 107/kg prior to freezing were selected.
Preparative Regimen
Pre-transplantation immunosuppressive therapy included oral hydroxyurea (30 mg/kg/d) and oral azathioprine (3 mg/kg/d) once a day for at least 90 days prior to transplantation. The conditioning regimen consisted of 50 mg/kg/d cyclophosphamide (CY) for 2 days (days -8, -7) followed by 40 mg/m2/d fludarabine (FLU) for 5 days (days -6, -5, -4, -3, -2), and 2.8 to 3.6 mg/kg/d busulfan (BU) for 3 days (days -6, -5, -4). BU dose was determined based on the risk assessment status. It was adjusted by testing the serum BU level to maintain a steady-state concentration between 600 and 800 μg/L17. Rabbit anti-thymocyte globulin (r-ATG, 1 mg/kg/d) was administered for 3 days (days -3, -2, -1). Thiotepa (TT, 10 mg/kg/d) was administered to 61 patients on day -3 (Supplemental Fig. S1). Notably, only three of the first 15 recipients received TT due to medication availability.
Post-Transplantation Immunosuppression
GVHD prophylaxis included PTCY (50 mg/kg/d, days +3 and +4) and a short course of methotrexate (10 mg/m2/d on day +7, then 7 mg/m2/d on days +9 and +12). Tacrolimus (0.04 mg/kg/d) was administered via continuous intravenous infusion over 24 h from day +5 until engraftment or until the patient was able to take oral prescriptions. Tacrolimus administration was targeted to maintain a level between and 5 to 15 ng/mL until day +180 and was then tapered unless there was evidence of acute GVHD (aGVHD) or chronic GVHD (cGVHD). Mycophenolate mofetil (MMF, 30 mg/kg/d) was administered intravenously every 8 h from day +6 onward and changed to an oral prescription until day +30. MMF was tapered after day +30 until day +60 unless signs of GVHD presented.
Supportive Care
Patients were treated in isolated units with high-efficiency particulate-free air filters under strict regulation. From day 8, all patients received an infusion of heparin (150 unit/kg/d) over 20 h and oral ursodeoxycholic acid (12 mg/kg/d) until +20 and +90 days, respectively, unless complications occurred. All patients received empiric broad-spectrum antibiotics to prevent septicemia until the resolution of neutropenia if there was no evidence of bacterial infection. Oral posaconazole (4-6 mg/kg/d) was administered as an anti-fungal prophylactic from day +3 to day +180 unless a fungal infection was evident. Oral sulfamethoxazole (25 to 50 mg/kg/d) was administered three days per week if the total white blood cell count exceeded 3 × 109/L until at least +90 days to prevent pneumocystis.
Patients were screened weekly for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia using a real-time PCR-based method until day +120, then at every return visit. Pre-emptive antiviral therapy was initiated if patient plasma CMV-DNA levels exceeded 1000 copies/ml or levels exceeded 400 copies/ml in combination with highly suspect symptoms of CMV disease. Ganciclovir was used as first-line treatment. Foscarnet was administered to patients suspected or confirmed to have drug-resistant CMV variant mutations. Patients with rising EBV-DNA copy numbers or lower levels of copy numbers with clinical evidence of a post-transplantation lymphoproliferative disorder (PTLD) were considered for intervention. Discontinuation of immunosuppressants was the first consideration. Rituximab (375 mg/m2) per week was administered for up to 28 days in patients with symptom progression. PTLD diagnosis was confirmed based on biopsies and radiological findings. Cytotoxic T lymphocyte (CTL) therapy against CMV or EBV was used in patients with a poor response to conventional treatment.
Patient Evaluations
All patients received high-volume blood transfusions at least 180 days prior to haplo-SCT to maintain a hemoglobin level over 100 g/L. Chelation therapy was conducted according to standard guidelines and a course of high-intensity chelation therapy consisting of a continuous infusion of deferoxamine over 18 h per day was applied to patients over four consecutive days to maintain a target serum ferritin level below 1000 ng/mL before transplantation. Donor-specific anti-HLA antibodies were assessed in patients who received haplo-SCT after January 2018. Patients with high donor-specific anti-HLA antibody titres were advised to change donors or receive treatment to reduce antibody titres as per the institutional protocol if there were no other available donors. Graft chimerism was assessed using a short-tandem-repeat (STR) polymerase chain reaction assay.
Definition of Engraftment
Myeloid engraftment was defined as the first day the absolute neutrophil count (ANC) exceeded 0.5 × 109/L for three consecutive days. Platelet engraftment was defined as the first day platelet count exceeded 20 × 1012/L for seven consecutive days. Primary graft failure was defined as an ANC below 0.5 × 109/L, hemoglobin below 80 g/L, and platelets below 20 × 1012/L by day +28. Secondary graft failure was defined as an ANC below 0.5 × 109/L after initial engraftment excluding primary disease, infection, or drug toxicity. Primary poor graft function (PGF) was defined as bilinear severe cytopenia with or without transfusion requirements after day +28 (which occurred in a situation of full-donor chimerism). Secondary PGF was defined as (1) severe cytopenia with two or three lines that developed after cell engraftment and lasted for over 30 days; (2) myelodysplasia (which occurred in a situation of full chimerism); and (3) excluding other causes of cytopenia27,28.
Statistical Methods
OS and transfusion-free survival (TFS) were calculated using the Kaplan-Meier estimator using GraphPad Prism (version 8) software. Patients that were alive and had not experienced any further events by August 31, 2020 were censored.
Results
Patient Characteristics
Patient characteristics are shown in Table 1. The median age was 7 years (range, 3 to 14 years) and the female: male ratio was 0.6. Haploidentical donors were the fathers, mothers, siblings, and other relatives of the recipient in 54%, 11%, 24%, and 1% of cases, respectively. Twenty-three (32%) of patients matched the ABO blood type of their donors. Recipients were matched to their donors for 5 (63%), 6 (21%), 7 (12%), and 8 (5%) HLA loci. Sixteen patients (22%) with an ABO blood type matching their haploidentical donors received both BM and GCSF-mobilized PBSCs. The remaining patients (78%) received only PBSCs from haploidentical donors.
Table 1. Patient Characteristics.
Patient characteristics
Total number
73
Median age at transplantation age (years, range)
7 (3 to 14)
Risk assessment
Low
2 (3%)
Intermediate
42 (57%)
High
29 (40%)
Sex
Female
27 (37%)
Male
46 (63%)
HLA matching
5/10
45 (62%)
6/10
15 (21%)
7/10
9 (12%)
8/10
4 (5%)
Donor
Brother
14 (19%)
Sister
10 (15%)
Father
39 (54%)
Mother
8 (11%)
Other relative
1 (1%)
ABO blood type
Matched
23 (32%)
Mismatched
50 (68%)
Stem cell source
PBSC alone
57 (78%)
PBSC + BM
16 (22%)
Stem cell engraftment
Haplo
43 (59%)
Cord blood
30 (41%)
MNC dose (108/kg) (median, range)
20 (10.60 to 32.20)
CD34+ dose (106/kg) (median, range)
15.45 (2.60 to 62.00)
Cell engraftment (median, range)
Days to neutrophil engraftment
22 (15 to 48)
Days to platelet engraftment
20 (8 to 99)
Primary or secondary graft failure
0
BM, bone marrow; HLA, human leukocyte antigen; MNC. mononucleated cells; PBSC, peripheral blood stem cell.
No primary or secondary graft failure was observed. Forty-three (59%) patients were engrafted with haploidentical grafts alone. The others (41%) were engrafted with cord blood or had mixed chimerism of both types of grafts. Notably, all patients with mixed chimerism of both haploidentical grafts and cord blood following the transplant eventually reached full engraftment of cord blood (STR > 99%) by 12 months after transplantation (Supplemental Fig. S2). The median CD34+ cell number of haploidentical grafts was 18.52 × 106/kg (range, 2.6 to 62 × 106/kg). The median time to myeloid and platelet engraftment was 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively.
GVHD and Other Complications
As shown in Table 2, 20 (27%) patients developed grade I to II aGVHD and 18 (25%) patients developed grade III to IV aGVHD. Eighteen of these patients received steroids against aGVHD in addition to standard GVHD prophylaxis. Twenty-seven (37%) patients developed cGVHD, but only one patient developed extensive cGVHD (grade III to IV).
Table 2. GVHD and Other Complications in Haplo-Cord Transplant Patients.
Complications Number of patients
Acute GVHD
38 (52%)
I to II
20 (27%)
III to IV
18 (25%)
Use of steroids
18
Chronic GVHD
27 (37%)
Mild
26 (36%)
Severe
1 (1%)
Infections
CMV-DNAemia
35 (48%)
CMV diseases
5 (7%)
EBV-DNAemia
19 (26%)
PTLD
5 (7%)
Herpetic zoster reactivation
6 (10%)
HHV6
1 (1%)
BKV related hemorrhagic cystitis
7 (9%)
Sepsis
3 (5%)
Tuberculosis
1 (1%)
Streptococcus meningitis
1 (1%)
Invasive fungal infection
7 (10%)
Other complications
Poor graft function (PGF)
6 (8%)
Primary PGF
4 (5%)
Secondary PGF
2 (3%)
SOS/VOD
6 (8%)
Mucositis
18 (25%)
Refractory autoimmune haemolytic anemia
1 (1%)
Cause of death
Chronic GVHD
1
Secondary PGF
1
Refractory autoimmune hemolytic anaemia
1
Follow up time (median, range)
811 (370 to 1433)
GVHD, graft versus host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; PTLD, post transplant lymphoproliferative disease; HHV6, type 6 human herpesvirus; BKV, BK virus; PGF, poor graft function; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.
Cytopenia was observed in 10% of patients. Four (5%) and two (3%) patients developed primary and secondary PGF, respectively. Eighteen patients (25%) developed grade III to IV mucositis. Six patients (8%) developed sinusoidal obstruction syndrome (SOS; previously known as veno-occlusive disease, VOD). Thirty-five (48%) patients had CMV-DNAemia (plasma CMV-DNA > 400 copies/ml) before day +100, but only five (7%) developed CMV disease. Nineteen (26%) patients had EBV-DNA and five (7%) developed PTLD. In addition, four patients with CMV infection and five with EBV infection received CTL therapy because they had a poor response to conventional treatment. Seven (9%) patients developed BK-virus-related hemorrhagic cystitis. Herpes zoster reactivation was observed in seven patients (10%) and one patient developed type 6 human herpesvirus (HHV6) encephalopathy. Four patients (5%) had septicaemia. Uncommon bacterial infections included one case of streptococcal meningitis and another case of systemic tuberculosis. Invasive fungal infections were observed in seven patients (10%). No patients in this report died of a severe infection.
Overall Survival and Transfusion-Free Survival
The estimated OS and TFS were both 95.26% (CI 95.77% to 96.23%) (Fig. 1). Three patients died during the follow-up. One patient had poor graft function and died of hyperacute intracranial hemorrhage on day +418. The other patient developed severe cGVHD and died of respiratory failure on day +370. The third patient died of refractory autoimmune hemolytic anaemia on day +658. The median follow-up period was 811 days (range, 370 to 1433 days).
Fig. 1. Engraftment of patients that received haploidentical grafts or cord blood. (A) Neutrophil and (B) platelet recovery in patients with haploidentical (Haplo) or cord blood (CB) engraftments (mean ± SD, Haplo vs. CB; (A) 21 ± 4 days vs. 30 ± 8 days and (B) 17 ± 7 days vs. 45 ± 25 days; ****p < 0.001, Mann-Whitney U test).
Cord Blood Contributed to Delayed Engraftment and Increased aGVHD Severity
Patient outcomes were compared between those engrafted with cord blood and those engrafted with haploidentical grafts (Fig. 2). Patients with cord blood engraftment required more time for neutrophil and platelet engraftment (****p < 0.0001, Mann-Whitney U test). Cord blood engraftment was also associated with a higher risk of developing grade III to IV aGVHD compared to patients engrafted with haploidentical grafts (**** p < 0.0001, Fisher’s exact test) (Fig. 3A). Interestingly, the rates of viral, bacterial, and fungal infections did not differ between patients with haploidentical grafts and cord blood engraftment (Fig. 3B). These two groups of patients did not differ in terms of survival and other complications after transplantation (data not shown).
Fig. 2. The estimated three-year overall survival (OS) and transfusion-free survival (TFS) for pediatric thalassemia major patients who received haplo-cord transplantations.
Fig. 3. Acute graft-versus-host disease (aGVHD) severity and viral DNAemia rates in patients engrafted with haploidentical grafts (Haplo) or cord blood (CB). (A) The severity of aGVHD in patients with Haplo or CB engraftments (****p < 0.001, Fisher’s exact test). (B) The number of patients with post-hematopoietic stem cell transplantation viral DNAemia in patients that received Haplo or CB engraftments (****p < 0.001, Fisher’s exact test).
Discussion
This is one of the largest studies of pediatric TM patients who received HSCT from alternative donors following a haplo-cord program. Patient outcomes in this study were outstanding, with both OS and TFS rates above 95% and no graft failure. According to the literature, the long-term OS and EFS for TM patients who undergo HSCT from related and unrelated donors ranges from 50% to over 90%, respectively29,30. Recent attempts have modified the haploidentical transplant program to reduce the intensity of chemotherapy and to manipulate haploidentical grafts and show encouraging outcomes in thalassemia patients10,15–17. However, these studies are based on small cohorts, have short follow-up periods, or include ex vivo procedures that are not feasible for most transplant centres in China13,30. This study describes an alternative approach to cure TM with promising outcomes.
Most TM patients in this study were classified as high-risk patients and considered to have a greater risk of developing drug-toxicity-related complications, particularly severe hepatobiliary complications such as SOS25,31,32. We chose to use a myeloablative conditioning regimen in the current protocol because TM patients had very active hematopoiesis in the BM and were more likely to experience graft failure13,14. Many transplant centers now use treosulfan as a lower toxicity substitute for BU33,34. In addition, other approaches using alternative drugs in place of cyclophosphamide, and using reduced intensity chemotherapy instead of myeloablative chemotherapy have also been introduced in TM recipients of matched related and unrelated donors35–37. This information can help to guide the modification of the current protocol in the future. Nevertheless, despite an intense combination of preparation regimens consisting of alkylators (CY, BU, TT, and FLU) being used in this study, the overall rates of drug-related complications were low and no patients experienced inevitable consequences after treatment.
As a part of GVHD prophylaxis, PTCY was used on days +3 and +4 and therefore could have affected haploidentical graft engraftment. Thus, cord blood was provided as a back-up stem cell source on day +6 to ensure engraftment. The percentage of patients with cord blood engraftment or mixed chimerism of both types of grafts was higher than expected because there was a far greater number of cells in the haploidentical graft than that in the cord blood. Patients with mixed chimerism of both the haploidentical graft and cord blood after engraftment eventually showed full cord blood engraftment (STR > 99%). However, the mechanism behind this is unknown. We suspect that PTCY may have damaged the stem cells in the haploidentical grafts38. Another hypothesis is that T cells in the cord blood are more naïve than PBSCs, which contain a more heterogeneous population of T cells23. Cord blood also contains a higher proportion of regulatory T cells that contribute to improved tolerance and long-term engraftment39–41.
A relatively higher proportion of patients developed CMV and EBV DNA after receiving a transplant. However, the current study considered viral DNAemia if a patient had plasma CMV-DNA or EBV-DNA titres above 400 copies/ml. This threshold is lower than the standards used in most centres42. The lower threshold was used to closely monitor the viral titers, and if required, start pre-emptive antiviral therapy early. In addition, the high rates of viral DNAemia were associated with delayed immune recovery due to a high proportion of cord blood engraftment. However, we did not find a significant difference in the rates of either CMV or EBV DNAemia between patients with haploidentical graft and cord blood engraftment. Overall, the percentage of patients who developed CMV disease or EBV-associated PTLD was acceptable compared to those of most previously published data.
The percentages of patients who developed aGVHD and severe aGVHD were higher than expected in patients with cord blood engraftment. We used a low dose of r-ATG (1 mg/kg/d) as the T cell depletion strategy and applied a classic PTCY strategy to intensify the anti-T cell response to prevent GVHD. We also prioritized the selection of non-maternal relatives owing to the higher incidence of GVHD in recipients that received material from maternal donors43. Patients with cord blood engraftment were at a higher risk of developing severe aGVHD (grade III-IV). Patients with cord blood engraftment also required more time for cell recovery. Cord blood engraftment is preferred in leukemia patients with a lower chance of relapse because of the graft-versus-leukemia effect44–48. However, this effect is not beneficial for HSCT recipients with non-malignant diseases such as TM. A potential solution is to use a higher ATG dose to enhance the depletion of early active T cells49. Although reduced-intensity chemotherapy may help limit haploidentical graft toxicity, it may not be intense enough for an anti-T cell effect to prevent GVHD. GCSF-mobilized PBSCs are also a risk factor for aGVHD because of the high volume of T lymphocytes in the haploidentical graft50. The number of CD34+ cells in the haploidentical graft was also correlated with aGVHD severity (not shown). A possible solution is to use BM instead of PBSC, or increase the proportion of BM in patients that received a combination of BM and PBSC because BM is generally considered a graft source with a lower incidence of both acute and chronic GVHD51. In the current study, 22% of patients received a combination of GCSF-primed BM and PBSC. However, no differences were observed in terms of the incidence of transplant-related complications and disease outcomes, probably due to the small sample size (not shown). Thus, the problem of whether to use BM alone or to increase the percentage of BM under the current protocol requires further investigations. In addition, ex vivo graft manipulation with depletion of αβ+ T cells or selection of CD34+ cells have shown to have lower rates of aGVHD and viral reactivation in TM patients that received haplo-SCT52,53. However, the incidence of graft failure can reach as high as 45% in these studies. The OS and disease-free survival are relatively low compared to studies without graft manipulation and the current data. Therefore, further investigations are required to balance between transplant-related complications and long-term survival and disease outcomes for TM patients.
Compared to other haplo-cord programs performed in malignant diseases54, cGVHD management in the current study was promising. In our study, most patients received only PBSCs from haploidentical donors. Although haplo-PBSC recipients have been correlated with a higher incidence of cGVHD compared to BM recipients49,55, we are satisfied with the current result; only a single patient developed extensive cGVHD.
Of the patients who did not survive, two were engrafted with cord blood. However, the precise correlation between cord blood engraftment and mortality was not calculated due to the small sample size in this study. Although we are satisfied with the overall outcomes resulting from the use of the current haplo-cord protocol, optimizations are required to minimize preventable complications. Future studies involving larger cohorts and longer terms are necessary to prove long-term efficacy.
Another limitation of this study is that the use of cord blood may burden patients and their families with additional cost, because of the relatively higher rates of aGVHD and viremia. However, the total cost of treatment for TM patients in our center is low (approximately 30,000 US dollars to 60,000 US dollars for the majority of patients) compared to data reported from developed countries56. Nevertheless, further proper clinical trial is required to study the cost effectiveness between centers using different haplo-HSCT protocols for TM patients.
In conclusion, the haplo-cord program is effective and safe for treating pediatric patients with TM. The fact that the haplo-cord program may minimize graft failure is a key strength of the current study. However, concerns regarding cord blood engraftment include the higher rates of severe aGVHD and longer period required for immune reconstitution. Further investigation is required to optimize the haplo-cord protocol to improve survival and limit severe complications.
Supplemental Material
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-png-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 - Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major
Click here for additional data file.
Supplemental Material, sj-tiff-1-cll-10.1177_0963689721994808 for Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major by Xiaodong Wang, Xiaoling Zhang, Uet Yu, Chunjing Wang, Chunlan Yang, Yue Li, Changgang Li, Feiqiu Wen, Chunfu Li and Sixi Liu in Cell Transplantation
Acknowledgments
We thank Prof. Kuang-Yueh Chiang at the Hospital for Sick Children in Toronto, Canada for constantly consulting our patients.
Ethical Approval: This study was approved by the human ethics committee at Shenzhen Children’s Hospital.
Statement of Human and Animal Rights: This study was conducted in accordance with the Helsinki Declaration for human studies.
Statement of Informed Consent: Written informed consents were obtained from the patients’ parents for the collection and publication of clinical data.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), and Shenzhen Key Medical Discipline Construction Fund (SZXK034).
ORCID iDs: Xiaoling Zhang
https://orcid.org/0000-0002-1940-0202
Uet Yu
https://orcid.org/0000-0003-4391-3398
Supplemental Material: Supplemental material for this article is available online. | AZATHIOPRINE, BUSULFAN, CYCLOPHOSPHAMIDE, FLUDARABINE PHOSPHATE, HYDROXYUREA, METHOTREXATE, MYCOPHENOLATE MOFETIL, TACROLIMUS, THIOTEPA | DrugsGivenReaction | CC BY-NC | 33593080 | 20,336,433 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac arrest'. | Vancomycin induced cardiac arrest: a case report.
BACKGROUND
Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and had a cardiac arrest.
METHODS
A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.
CONCLUSIONS
Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
Background
Preoperative antibiotic prophylaxis has become a standard practice, in patients who will have an artificial implant or foreign body implanted as part of the procedure [1]. Vancomycin is one such antibiotic that is used for both prevention and treatment of infections caused by gram-positive bacteria predominantly staphylococcal infections, which is commonly encountered in orthopedic practice. However the use of intravenous vancomycin demands extreme caution, as accidental rapid infusion can precipitate Red Man Syndrome (RMS) that can be life-threatening, if not identified and managed aptly. In this case report, we aim to highlight this rare and yet dreadful adverse effect of vancomycin, that can occur in daily clinical practice.
Case presentation
We recount of a 9-year-old Asian girl diagnosed with Ewing’s sarcoma of left distal tibia. She had received six cycles of chemotherapy that had reduced the size of periosteal lesion compared to few months back. So she was planned for wide resection of the tumor along with reconstruction of her leg. To prevent the risks of implant associated infection, it was decided that the bone cement used during surgery would be impregnated with vancomycin. Following a routine pre-anesthetic assessment, she was cleared for surgery.
A night before the surgery at around 10 pm, an order of prophylactic intravenous vancomycin 500 milligram (mg) in 100 milliliters (mls) of 0.9% normal saline (NS) over 1 hour was carried out in the orthopedic ward. However the drug was accidently infused in about 5 minutes. Soon the patient was restless, complained of epigastric discomfort along with suffocation and feeling of tightness in her chest and neck. There was visible flushing of her face. Within a matter of seconds, she was dyspneic with oxygen saturation falling to 40% along with drop in blood pressure to 40/20 millimeters of mercury (mm Hg). Suddenly her respiration ceased and carotid pulse was impalpable. Immediately chest compression was initiated along with bag and mask ventilation. 0.9% NS was infused rapidly. The patient’s trachea was intubated and ventilation continued. There was return of spontaneous circulation (ROSC) after a minute of chest compressions. Following ROSC, her heart rate was 140 beats per minute in sinus rhythm, oxygen saturation of 99 % with oxygen and blood pressure of 120/90 mm of Hg with Glasgow coma scale (GCS) of E4M5Vt. She was given an injection of pheniramine 10 mg and hydrocortisone 50 mg intravenously. On auscultation of chest, there was decreased air entry bilaterally along with expiratory wheeze that resolved with salbutamol nebulization. She was shifted to Intensive care unit (ICU) where respiration was controlled by mechanical ventilation overnight under sedation. A chest x-ray done was normal. Overnight there were no issues to be addressed and was planned for gradual tapering of sedation. In the morning, she gradually gained full consciousness with normal arterial blood gas analysis and blood reports. The patient’s trachea was extubated following a successful spontaneous breathing trial with T-piece. She was discharged from ICU in the evening with resumption of normal feeding and discharged from the hospital a day after.
The child was admitted again three weeks later and underwent the contemplated procedure uneventfully.
Discussion
The prescription of antibiotics is inevitable and with it its unwanted adverse effects. Vancomycin use brings to the table the risks of two hypersensitivity reaction namely anaphylaxis and Red Man Syndrome [2, 3]. While it is a daunting task to differentiate anaphylaxis from RMS clinically, the latter is believed to be related to the rate of intravenous infusion and it being the more common reaction between the two [3]. RMS, an anaphylactoid reaction, owes it effects to histamine release following mast cell degranulation whereas anaphylaxis is Ig-E mediated. Role of plasma tryptase to differentiate the two reaction is doubtful. RMS is seen in 3.7 to 47% in infected patients and up to 90% in healthy volunteers [3]. Patients younger than the age of 40, particularly children are vulnerable to its severe form [4]. In children receiving vancomycin, the prevalence of RMS is 14% [5]. The dictum with vancomycin infusion has always been to do so slowly and carefully. However, in our case inadvertent rapid infusion of vancomycin lead to a life threatening situation.
RMS presents with generalized flushing, pruritus and erythematous rash affecting the upper body, neck, and face. In its severe form, dyspnoea, chest discomfort and hypotension can occur. Hypotension without the appearance of a rash has also been reported [6]. RMS is rarely life-threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [6–8]. Our patient had brief flushing of her face with respiratory distress and hypotension which eventually progressed to cardiac-respiratory arrest. We did not look for rashes as cardiopulmonary resuscitation was started immediately and by the time the patient became stable, no flushing and rashes were noted.
RMS is a consequence of histamine release from mast cells and basophils located in the skin, lung, gastrointestinal tract, myocardium, and vascular system [3]. Histamine release occurs as a result of interaction of vancomycin with Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2), a G-protein-coupled receptor mediating Ig-E independent mast cell degranulation [9, 10]. The fact that pretreatment with antihistamines has shown to reduce the effects of RMS further supports the histamine mediated mechanism [11]. The severity of reaction is proportional to the amount of histamine release [3]. Signs and symptoms may occur after 4–10 minutes of intravenous infusion or after its completion and even further delayed presentation have been reported [12].
Although commonly encountered with parenteral use of vancomycin, RMS has also been reported, when used in oral form [13], powder form [13] and vancomycin loaded bone cement [14]. Other antibiotics such as ciprofloxacin, amphotericin B, rifampin, and teicoplanin are also potentially linked with RMS [15]. The concomitant use of opioid analgesics, muscle relaxants, contrast dye with vancomycin seems to augment the effects of RMS [12]. Our patient did not receive any such medications and a link between past use of chemotherapy and vancomycin could not be established.
Vigilance during vancomycin infusion can identify any untoward reaction and warrant intervention. It is recommended to administer intravenous vancomycin over one to two hours duration preferably using volumetric pump with infusion rate not exceeding 10 mg/min [6] Pretreatment with antihistamines may reduce the incidence and severity of RMS [6, 11]. The infusion should be stopped right away when features of RMS is noticed and antihistamines prescribed to treat them. Corticosteroids can come to rescue in refractory cases. Occasionally, there may be the need to maintain circulation with intravenous fluids and ensure adequate oxygenation to stabilize the hemodynamics. Vancomycin desensitization is suggested in patients where the classical treatment modality is unable to stop RMS and there is the absolute need to continue vancomycin [3].
Conclusion
Vancomycin use in perioperative period is ever flourishing. This report sheds light to a rare adverse effect that can be encountered with its use. However awareness among healthcare practitioners and a well-designed protocol about the vancomycin infusion will prove worthwhile.
Abbreviations
GCSGlasgow coma scale
ICUIntensive care unit
MgMilligram
MlMilliliters
Mm of HgMillimeters of mercury
MRGPRX2Mas-related G-protein-coupled receptor X2
NSNormal saline
ROSCReturn of spontaneous circulation
RMSRed Man Syndrome
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contribution
SK was directly involved in management of the patient. He collected relevant information, designed, drafted, edited the report. SR was also involved in patient management and revised the report. Both authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | VANCOMYCIN | DrugsGivenReaction | CC BY | 33593409 | 18,972,960 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardio-respiratory arrest'. | Vancomycin induced cardiac arrest: a case report.
BACKGROUND
Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and had a cardiac arrest.
METHODS
A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.
CONCLUSIONS
Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
Background
Preoperative antibiotic prophylaxis has become a standard practice, in patients who will have an artificial implant or foreign body implanted as part of the procedure [1]. Vancomycin is one such antibiotic that is used for both prevention and treatment of infections caused by gram-positive bacteria predominantly staphylococcal infections, which is commonly encountered in orthopedic practice. However the use of intravenous vancomycin demands extreme caution, as accidental rapid infusion can precipitate Red Man Syndrome (RMS) that can be life-threatening, if not identified and managed aptly. In this case report, we aim to highlight this rare and yet dreadful adverse effect of vancomycin, that can occur in daily clinical practice.
Case presentation
We recount of a 9-year-old Asian girl diagnosed with Ewing’s sarcoma of left distal tibia. She had received six cycles of chemotherapy that had reduced the size of periosteal lesion compared to few months back. So she was planned for wide resection of the tumor along with reconstruction of her leg. To prevent the risks of implant associated infection, it was decided that the bone cement used during surgery would be impregnated with vancomycin. Following a routine pre-anesthetic assessment, she was cleared for surgery.
A night before the surgery at around 10 pm, an order of prophylactic intravenous vancomycin 500 milligram (mg) in 100 milliliters (mls) of 0.9% normal saline (NS) over 1 hour was carried out in the orthopedic ward. However the drug was accidently infused in about 5 minutes. Soon the patient was restless, complained of epigastric discomfort along with suffocation and feeling of tightness in her chest and neck. There was visible flushing of her face. Within a matter of seconds, she was dyspneic with oxygen saturation falling to 40% along with drop in blood pressure to 40/20 millimeters of mercury (mm Hg). Suddenly her respiration ceased and carotid pulse was impalpable. Immediately chest compression was initiated along with bag and mask ventilation. 0.9% NS was infused rapidly. The patient’s trachea was intubated and ventilation continued. There was return of spontaneous circulation (ROSC) after a minute of chest compressions. Following ROSC, her heart rate was 140 beats per minute in sinus rhythm, oxygen saturation of 99 % with oxygen and blood pressure of 120/90 mm of Hg with Glasgow coma scale (GCS) of E4M5Vt. She was given an injection of pheniramine 10 mg and hydrocortisone 50 mg intravenously. On auscultation of chest, there was decreased air entry bilaterally along with expiratory wheeze that resolved with salbutamol nebulization. She was shifted to Intensive care unit (ICU) where respiration was controlled by mechanical ventilation overnight under sedation. A chest x-ray done was normal. Overnight there were no issues to be addressed and was planned for gradual tapering of sedation. In the morning, she gradually gained full consciousness with normal arterial blood gas analysis and blood reports. The patient’s trachea was extubated following a successful spontaneous breathing trial with T-piece. She was discharged from ICU in the evening with resumption of normal feeding and discharged from the hospital a day after.
The child was admitted again three weeks later and underwent the contemplated procedure uneventfully.
Discussion
The prescription of antibiotics is inevitable and with it its unwanted adverse effects. Vancomycin use brings to the table the risks of two hypersensitivity reaction namely anaphylaxis and Red Man Syndrome [2, 3]. While it is a daunting task to differentiate anaphylaxis from RMS clinically, the latter is believed to be related to the rate of intravenous infusion and it being the more common reaction between the two [3]. RMS, an anaphylactoid reaction, owes it effects to histamine release following mast cell degranulation whereas anaphylaxis is Ig-E mediated. Role of plasma tryptase to differentiate the two reaction is doubtful. RMS is seen in 3.7 to 47% in infected patients and up to 90% in healthy volunteers [3]. Patients younger than the age of 40, particularly children are vulnerable to its severe form [4]. In children receiving vancomycin, the prevalence of RMS is 14% [5]. The dictum with vancomycin infusion has always been to do so slowly and carefully. However, in our case inadvertent rapid infusion of vancomycin lead to a life threatening situation.
RMS presents with generalized flushing, pruritus and erythematous rash affecting the upper body, neck, and face. In its severe form, dyspnoea, chest discomfort and hypotension can occur. Hypotension without the appearance of a rash has also been reported [6]. RMS is rarely life-threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [6–8]. Our patient had brief flushing of her face with respiratory distress and hypotension which eventually progressed to cardiac-respiratory arrest. We did not look for rashes as cardiopulmonary resuscitation was started immediately and by the time the patient became stable, no flushing and rashes were noted.
RMS is a consequence of histamine release from mast cells and basophils located in the skin, lung, gastrointestinal tract, myocardium, and vascular system [3]. Histamine release occurs as a result of interaction of vancomycin with Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2), a G-protein-coupled receptor mediating Ig-E independent mast cell degranulation [9, 10]. The fact that pretreatment with antihistamines has shown to reduce the effects of RMS further supports the histamine mediated mechanism [11]. The severity of reaction is proportional to the amount of histamine release [3]. Signs and symptoms may occur after 4–10 minutes of intravenous infusion or after its completion and even further delayed presentation have been reported [12].
Although commonly encountered with parenteral use of vancomycin, RMS has also been reported, when used in oral form [13], powder form [13] and vancomycin loaded bone cement [14]. Other antibiotics such as ciprofloxacin, amphotericin B, rifampin, and teicoplanin are also potentially linked with RMS [15]. The concomitant use of opioid analgesics, muscle relaxants, contrast dye with vancomycin seems to augment the effects of RMS [12]. Our patient did not receive any such medications and a link between past use of chemotherapy and vancomycin could not be established.
Vigilance during vancomycin infusion can identify any untoward reaction and warrant intervention. It is recommended to administer intravenous vancomycin over one to two hours duration preferably using volumetric pump with infusion rate not exceeding 10 mg/min [6] Pretreatment with antihistamines may reduce the incidence and severity of RMS [6, 11]. The infusion should be stopped right away when features of RMS is noticed and antihistamines prescribed to treat them. Corticosteroids can come to rescue in refractory cases. Occasionally, there may be the need to maintain circulation with intravenous fluids and ensure adequate oxygenation to stabilize the hemodynamics. Vancomycin desensitization is suggested in patients where the classical treatment modality is unable to stop RMS and there is the absolute need to continue vancomycin [3].
Conclusion
Vancomycin use in perioperative period is ever flourishing. This report sheds light to a rare adverse effect that can be encountered with its use. However awareness among healthcare practitioners and a well-designed protocol about the vancomycin infusion will prove worthwhile.
Abbreviations
GCSGlasgow coma scale
ICUIntensive care unit
MgMilligram
MlMilliliters
Mm of HgMillimeters of mercury
MRGPRX2Mas-related G-protein-coupled receptor X2
NSNormal saline
ROSCReturn of spontaneous circulation
RMSRed Man Syndrome
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contribution
SK was directly involved in management of the patient. He collected relevant information, designed, drafted, edited the report. SR was also involved in patient management and revised the report. Both authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33593409 | 19,721,726 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Depressed level of consciousness'. | Vancomycin induced cardiac arrest: a case report.
BACKGROUND
Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and had a cardiac arrest.
METHODS
A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.
CONCLUSIONS
Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
Background
Preoperative antibiotic prophylaxis has become a standard practice, in patients who will have an artificial implant or foreign body implanted as part of the procedure [1]. Vancomycin is one such antibiotic that is used for both prevention and treatment of infections caused by gram-positive bacteria predominantly staphylococcal infections, which is commonly encountered in orthopedic practice. However the use of intravenous vancomycin demands extreme caution, as accidental rapid infusion can precipitate Red Man Syndrome (RMS) that can be life-threatening, if not identified and managed aptly. In this case report, we aim to highlight this rare and yet dreadful adverse effect of vancomycin, that can occur in daily clinical practice.
Case presentation
We recount of a 9-year-old Asian girl diagnosed with Ewing’s sarcoma of left distal tibia. She had received six cycles of chemotherapy that had reduced the size of periosteal lesion compared to few months back. So she was planned for wide resection of the tumor along with reconstruction of her leg. To prevent the risks of implant associated infection, it was decided that the bone cement used during surgery would be impregnated with vancomycin. Following a routine pre-anesthetic assessment, she was cleared for surgery.
A night before the surgery at around 10 pm, an order of prophylactic intravenous vancomycin 500 milligram (mg) in 100 milliliters (mls) of 0.9% normal saline (NS) over 1 hour was carried out in the orthopedic ward. However the drug was accidently infused in about 5 minutes. Soon the patient was restless, complained of epigastric discomfort along with suffocation and feeling of tightness in her chest and neck. There was visible flushing of her face. Within a matter of seconds, she was dyspneic with oxygen saturation falling to 40% along with drop in blood pressure to 40/20 millimeters of mercury (mm Hg). Suddenly her respiration ceased and carotid pulse was impalpable. Immediately chest compression was initiated along with bag and mask ventilation. 0.9% NS was infused rapidly. The patient’s trachea was intubated and ventilation continued. There was return of spontaneous circulation (ROSC) after a minute of chest compressions. Following ROSC, her heart rate was 140 beats per minute in sinus rhythm, oxygen saturation of 99 % with oxygen and blood pressure of 120/90 mm of Hg with Glasgow coma scale (GCS) of E4M5Vt. She was given an injection of pheniramine 10 mg and hydrocortisone 50 mg intravenously. On auscultation of chest, there was decreased air entry bilaterally along with expiratory wheeze that resolved with salbutamol nebulization. She was shifted to Intensive care unit (ICU) where respiration was controlled by mechanical ventilation overnight under sedation. A chest x-ray done was normal. Overnight there were no issues to be addressed and was planned for gradual tapering of sedation. In the morning, she gradually gained full consciousness with normal arterial blood gas analysis and blood reports. The patient’s trachea was extubated following a successful spontaneous breathing trial with T-piece. She was discharged from ICU in the evening with resumption of normal feeding and discharged from the hospital a day after.
The child was admitted again three weeks later and underwent the contemplated procedure uneventfully.
Discussion
The prescription of antibiotics is inevitable and with it its unwanted adverse effects. Vancomycin use brings to the table the risks of two hypersensitivity reaction namely anaphylaxis and Red Man Syndrome [2, 3]. While it is a daunting task to differentiate anaphylaxis from RMS clinically, the latter is believed to be related to the rate of intravenous infusion and it being the more common reaction between the two [3]. RMS, an anaphylactoid reaction, owes it effects to histamine release following mast cell degranulation whereas anaphylaxis is Ig-E mediated. Role of plasma tryptase to differentiate the two reaction is doubtful. RMS is seen in 3.7 to 47% in infected patients and up to 90% in healthy volunteers [3]. Patients younger than the age of 40, particularly children are vulnerable to its severe form [4]. In children receiving vancomycin, the prevalence of RMS is 14% [5]. The dictum with vancomycin infusion has always been to do so slowly and carefully. However, in our case inadvertent rapid infusion of vancomycin lead to a life threatening situation.
RMS presents with generalized flushing, pruritus and erythematous rash affecting the upper body, neck, and face. In its severe form, dyspnoea, chest discomfort and hypotension can occur. Hypotension without the appearance of a rash has also been reported [6]. RMS is rarely life-threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [6–8]. Our patient had brief flushing of her face with respiratory distress and hypotension which eventually progressed to cardiac-respiratory arrest. We did not look for rashes as cardiopulmonary resuscitation was started immediately and by the time the patient became stable, no flushing and rashes were noted.
RMS is a consequence of histamine release from mast cells and basophils located in the skin, lung, gastrointestinal tract, myocardium, and vascular system [3]. Histamine release occurs as a result of interaction of vancomycin with Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2), a G-protein-coupled receptor mediating Ig-E independent mast cell degranulation [9, 10]. The fact that pretreatment with antihistamines has shown to reduce the effects of RMS further supports the histamine mediated mechanism [11]. The severity of reaction is proportional to the amount of histamine release [3]. Signs and symptoms may occur after 4–10 minutes of intravenous infusion or after its completion and even further delayed presentation have been reported [12].
Although commonly encountered with parenteral use of vancomycin, RMS has also been reported, when used in oral form [13], powder form [13] and vancomycin loaded bone cement [14]. Other antibiotics such as ciprofloxacin, amphotericin B, rifampin, and teicoplanin are also potentially linked with RMS [15]. The concomitant use of opioid analgesics, muscle relaxants, contrast dye with vancomycin seems to augment the effects of RMS [12]. Our patient did not receive any such medications and a link between past use of chemotherapy and vancomycin could not be established.
Vigilance during vancomycin infusion can identify any untoward reaction and warrant intervention. It is recommended to administer intravenous vancomycin over one to two hours duration preferably using volumetric pump with infusion rate not exceeding 10 mg/min [6] Pretreatment with antihistamines may reduce the incidence and severity of RMS [6, 11]. The infusion should be stopped right away when features of RMS is noticed and antihistamines prescribed to treat them. Corticosteroids can come to rescue in refractory cases. Occasionally, there may be the need to maintain circulation with intravenous fluids and ensure adequate oxygenation to stabilize the hemodynamics. Vancomycin desensitization is suggested in patients where the classical treatment modality is unable to stop RMS and there is the absolute need to continue vancomycin [3].
Conclusion
Vancomycin use in perioperative period is ever flourishing. This report sheds light to a rare adverse effect that can be encountered with its use. However awareness among healthcare practitioners and a well-designed protocol about the vancomycin infusion will prove worthwhile.
Abbreviations
GCSGlasgow coma scale
ICUIntensive care unit
MgMilligram
MlMilliliters
Mm of HgMillimeters of mercury
MRGPRX2Mas-related G-protein-coupled receptor X2
NSNormal saline
ROSCReturn of spontaneous circulation
RMSRed Man Syndrome
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contribution
SK was directly involved in management of the patient. He collected relevant information, designed, drafted, edited the report. SR was also involved in patient management and revised the report. Both authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33593409 | 19,721,726 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Incorrect drug administration rate'. | Vancomycin induced cardiac arrest: a case report.
BACKGROUND
Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and had a cardiac arrest.
METHODS
A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.
CONCLUSIONS
Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
Background
Preoperative antibiotic prophylaxis has become a standard practice, in patients who will have an artificial implant or foreign body implanted as part of the procedure [1]. Vancomycin is one such antibiotic that is used for both prevention and treatment of infections caused by gram-positive bacteria predominantly staphylococcal infections, which is commonly encountered in orthopedic practice. However the use of intravenous vancomycin demands extreme caution, as accidental rapid infusion can precipitate Red Man Syndrome (RMS) that can be life-threatening, if not identified and managed aptly. In this case report, we aim to highlight this rare and yet dreadful adverse effect of vancomycin, that can occur in daily clinical practice.
Case presentation
We recount of a 9-year-old Asian girl diagnosed with Ewing’s sarcoma of left distal tibia. She had received six cycles of chemotherapy that had reduced the size of periosteal lesion compared to few months back. So she was planned for wide resection of the tumor along with reconstruction of her leg. To prevent the risks of implant associated infection, it was decided that the bone cement used during surgery would be impregnated with vancomycin. Following a routine pre-anesthetic assessment, she was cleared for surgery.
A night before the surgery at around 10 pm, an order of prophylactic intravenous vancomycin 500 milligram (mg) in 100 milliliters (mls) of 0.9% normal saline (NS) over 1 hour was carried out in the orthopedic ward. However the drug was accidently infused in about 5 minutes. Soon the patient was restless, complained of epigastric discomfort along with suffocation and feeling of tightness in her chest and neck. There was visible flushing of her face. Within a matter of seconds, she was dyspneic with oxygen saturation falling to 40% along with drop in blood pressure to 40/20 millimeters of mercury (mm Hg). Suddenly her respiration ceased and carotid pulse was impalpable. Immediately chest compression was initiated along with bag and mask ventilation. 0.9% NS was infused rapidly. The patient’s trachea was intubated and ventilation continued. There was return of spontaneous circulation (ROSC) after a minute of chest compressions. Following ROSC, her heart rate was 140 beats per minute in sinus rhythm, oxygen saturation of 99 % with oxygen and blood pressure of 120/90 mm of Hg with Glasgow coma scale (GCS) of E4M5Vt. She was given an injection of pheniramine 10 mg and hydrocortisone 50 mg intravenously. On auscultation of chest, there was decreased air entry bilaterally along with expiratory wheeze that resolved with salbutamol nebulization. She was shifted to Intensive care unit (ICU) where respiration was controlled by mechanical ventilation overnight under sedation. A chest x-ray done was normal. Overnight there were no issues to be addressed and was planned for gradual tapering of sedation. In the morning, she gradually gained full consciousness with normal arterial blood gas analysis and blood reports. The patient’s trachea was extubated following a successful spontaneous breathing trial with T-piece. She was discharged from ICU in the evening with resumption of normal feeding and discharged from the hospital a day after.
The child was admitted again three weeks later and underwent the contemplated procedure uneventfully.
Discussion
The prescription of antibiotics is inevitable and with it its unwanted adverse effects. Vancomycin use brings to the table the risks of two hypersensitivity reaction namely anaphylaxis and Red Man Syndrome [2, 3]. While it is a daunting task to differentiate anaphylaxis from RMS clinically, the latter is believed to be related to the rate of intravenous infusion and it being the more common reaction between the two [3]. RMS, an anaphylactoid reaction, owes it effects to histamine release following mast cell degranulation whereas anaphylaxis is Ig-E mediated. Role of plasma tryptase to differentiate the two reaction is doubtful. RMS is seen in 3.7 to 47% in infected patients and up to 90% in healthy volunteers [3]. Patients younger than the age of 40, particularly children are vulnerable to its severe form [4]. In children receiving vancomycin, the prevalence of RMS is 14% [5]. The dictum with vancomycin infusion has always been to do so slowly and carefully. However, in our case inadvertent rapid infusion of vancomycin lead to a life threatening situation.
RMS presents with generalized flushing, pruritus and erythematous rash affecting the upper body, neck, and face. In its severe form, dyspnoea, chest discomfort and hypotension can occur. Hypotension without the appearance of a rash has also been reported [6]. RMS is rarely life-threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [6–8]. Our patient had brief flushing of her face with respiratory distress and hypotension which eventually progressed to cardiac-respiratory arrest. We did not look for rashes as cardiopulmonary resuscitation was started immediately and by the time the patient became stable, no flushing and rashes were noted.
RMS is a consequence of histamine release from mast cells and basophils located in the skin, lung, gastrointestinal tract, myocardium, and vascular system [3]. Histamine release occurs as a result of interaction of vancomycin with Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2), a G-protein-coupled receptor mediating Ig-E independent mast cell degranulation [9, 10]. The fact that pretreatment with antihistamines has shown to reduce the effects of RMS further supports the histamine mediated mechanism [11]. The severity of reaction is proportional to the amount of histamine release [3]. Signs and symptoms may occur after 4–10 minutes of intravenous infusion or after its completion and even further delayed presentation have been reported [12].
Although commonly encountered with parenteral use of vancomycin, RMS has also been reported, when used in oral form [13], powder form [13] and vancomycin loaded bone cement [14]. Other antibiotics such as ciprofloxacin, amphotericin B, rifampin, and teicoplanin are also potentially linked with RMS [15]. The concomitant use of opioid analgesics, muscle relaxants, contrast dye with vancomycin seems to augment the effects of RMS [12]. Our patient did not receive any such medications and a link between past use of chemotherapy and vancomycin could not be established.
Vigilance during vancomycin infusion can identify any untoward reaction and warrant intervention. It is recommended to administer intravenous vancomycin over one to two hours duration preferably using volumetric pump with infusion rate not exceeding 10 mg/min [6] Pretreatment with antihistamines may reduce the incidence and severity of RMS [6, 11]. The infusion should be stopped right away when features of RMS is noticed and antihistamines prescribed to treat them. Corticosteroids can come to rescue in refractory cases. Occasionally, there may be the need to maintain circulation with intravenous fluids and ensure adequate oxygenation to stabilize the hemodynamics. Vancomycin desensitization is suggested in patients where the classical treatment modality is unable to stop RMS and there is the absolute need to continue vancomycin [3].
Conclusion
Vancomycin use in perioperative period is ever flourishing. This report sheds light to a rare adverse effect that can be encountered with its use. However awareness among healthcare practitioners and a well-designed protocol about the vancomycin infusion will prove worthwhile.
Abbreviations
GCSGlasgow coma scale
ICUIntensive care unit
MgMilligram
MlMilliliters
Mm of HgMillimeters of mercury
MRGPRX2Mas-related G-protein-coupled receptor X2
NSNormal saline
ROSCReturn of spontaneous circulation
RMSRed Man Syndrome
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contribution
SK was directly involved in management of the patient. He collected relevant information, designed, drafted, edited the report. SR was also involved in patient management and revised the report. Both authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33593409 | 19,721,726 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Incorrect product administration duration'. | Vancomycin induced cardiac arrest: a case report.
BACKGROUND
Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and had a cardiac arrest.
METHODS
A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.
CONCLUSIONS
Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
Background
Preoperative antibiotic prophylaxis has become a standard practice, in patients who will have an artificial implant or foreign body implanted as part of the procedure [1]. Vancomycin is one such antibiotic that is used for both prevention and treatment of infections caused by gram-positive bacteria predominantly staphylococcal infections, which is commonly encountered in orthopedic practice. However the use of intravenous vancomycin demands extreme caution, as accidental rapid infusion can precipitate Red Man Syndrome (RMS) that can be life-threatening, if not identified and managed aptly. In this case report, we aim to highlight this rare and yet dreadful adverse effect of vancomycin, that can occur in daily clinical practice.
Case presentation
We recount of a 9-year-old Asian girl diagnosed with Ewing’s sarcoma of left distal tibia. She had received six cycles of chemotherapy that had reduced the size of periosteal lesion compared to few months back. So she was planned for wide resection of the tumor along with reconstruction of her leg. To prevent the risks of implant associated infection, it was decided that the bone cement used during surgery would be impregnated with vancomycin. Following a routine pre-anesthetic assessment, she was cleared for surgery.
A night before the surgery at around 10 pm, an order of prophylactic intravenous vancomycin 500 milligram (mg) in 100 milliliters (mls) of 0.9% normal saline (NS) over 1 hour was carried out in the orthopedic ward. However the drug was accidently infused in about 5 minutes. Soon the patient was restless, complained of epigastric discomfort along with suffocation and feeling of tightness in her chest and neck. There was visible flushing of her face. Within a matter of seconds, she was dyspneic with oxygen saturation falling to 40% along with drop in blood pressure to 40/20 millimeters of mercury (mm Hg). Suddenly her respiration ceased and carotid pulse was impalpable. Immediately chest compression was initiated along with bag and mask ventilation. 0.9% NS was infused rapidly. The patient’s trachea was intubated and ventilation continued. There was return of spontaneous circulation (ROSC) after a minute of chest compressions. Following ROSC, her heart rate was 140 beats per minute in sinus rhythm, oxygen saturation of 99 % with oxygen and blood pressure of 120/90 mm of Hg with Glasgow coma scale (GCS) of E4M5Vt. She was given an injection of pheniramine 10 mg and hydrocortisone 50 mg intravenously. On auscultation of chest, there was decreased air entry bilaterally along with expiratory wheeze that resolved with salbutamol nebulization. She was shifted to Intensive care unit (ICU) where respiration was controlled by mechanical ventilation overnight under sedation. A chest x-ray done was normal. Overnight there were no issues to be addressed and was planned for gradual tapering of sedation. In the morning, she gradually gained full consciousness with normal arterial blood gas analysis and blood reports. The patient’s trachea was extubated following a successful spontaneous breathing trial with T-piece. She was discharged from ICU in the evening with resumption of normal feeding and discharged from the hospital a day after.
The child was admitted again three weeks later and underwent the contemplated procedure uneventfully.
Discussion
The prescription of antibiotics is inevitable and with it its unwanted adverse effects. Vancomycin use brings to the table the risks of two hypersensitivity reaction namely anaphylaxis and Red Man Syndrome [2, 3]. While it is a daunting task to differentiate anaphylaxis from RMS clinically, the latter is believed to be related to the rate of intravenous infusion and it being the more common reaction between the two [3]. RMS, an anaphylactoid reaction, owes it effects to histamine release following mast cell degranulation whereas anaphylaxis is Ig-E mediated. Role of plasma tryptase to differentiate the two reaction is doubtful. RMS is seen in 3.7 to 47% in infected patients and up to 90% in healthy volunteers [3]. Patients younger than the age of 40, particularly children are vulnerable to its severe form [4]. In children receiving vancomycin, the prevalence of RMS is 14% [5]. The dictum with vancomycin infusion has always been to do so slowly and carefully. However, in our case inadvertent rapid infusion of vancomycin lead to a life threatening situation.
RMS presents with generalized flushing, pruritus and erythematous rash affecting the upper body, neck, and face. In its severe form, dyspnoea, chest discomfort and hypotension can occur. Hypotension without the appearance of a rash has also been reported [6]. RMS is rarely life-threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [6–8]. Our patient had brief flushing of her face with respiratory distress and hypotension which eventually progressed to cardiac-respiratory arrest. We did not look for rashes as cardiopulmonary resuscitation was started immediately and by the time the patient became stable, no flushing and rashes were noted.
RMS is a consequence of histamine release from mast cells and basophils located in the skin, lung, gastrointestinal tract, myocardium, and vascular system [3]. Histamine release occurs as a result of interaction of vancomycin with Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2), a G-protein-coupled receptor mediating Ig-E independent mast cell degranulation [9, 10]. The fact that pretreatment with antihistamines has shown to reduce the effects of RMS further supports the histamine mediated mechanism [11]. The severity of reaction is proportional to the amount of histamine release [3]. Signs and symptoms may occur after 4–10 minutes of intravenous infusion or after its completion and even further delayed presentation have been reported [12].
Although commonly encountered with parenteral use of vancomycin, RMS has also been reported, when used in oral form [13], powder form [13] and vancomycin loaded bone cement [14]. Other antibiotics such as ciprofloxacin, amphotericin B, rifampin, and teicoplanin are also potentially linked with RMS [15]. The concomitant use of opioid analgesics, muscle relaxants, contrast dye with vancomycin seems to augment the effects of RMS [12]. Our patient did not receive any such medications and a link between past use of chemotherapy and vancomycin could not be established.
Vigilance during vancomycin infusion can identify any untoward reaction and warrant intervention. It is recommended to administer intravenous vancomycin over one to two hours duration preferably using volumetric pump with infusion rate not exceeding 10 mg/min [6] Pretreatment with antihistamines may reduce the incidence and severity of RMS [6, 11]. The infusion should be stopped right away when features of RMS is noticed and antihistamines prescribed to treat them. Corticosteroids can come to rescue in refractory cases. Occasionally, there may be the need to maintain circulation with intravenous fluids and ensure adequate oxygenation to stabilize the hemodynamics. Vancomycin desensitization is suggested in patients where the classical treatment modality is unable to stop RMS and there is the absolute need to continue vancomycin [3].
Conclusion
Vancomycin use in perioperative period is ever flourishing. This report sheds light to a rare adverse effect that can be encountered with its use. However awareness among healthcare practitioners and a well-designed protocol about the vancomycin infusion will prove worthwhile.
Abbreviations
GCSGlasgow coma scale
ICUIntensive care unit
MgMilligram
MlMilliliters
Mm of HgMillimeters of mercury
MRGPRX2Mas-related G-protein-coupled receptor X2
NSNormal saline
ROSCReturn of spontaneous circulation
RMSRed Man Syndrome
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contribution
SK was directly involved in management of the patient. He collected relevant information, designed, drafted, edited the report. SR was also involved in patient management and revised the report. Both authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | VANCOMYCIN | DrugsGivenReaction | CC BY | 33593409 | 18,972,960 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Red man syndrome'. | Vancomycin induced cardiac arrest: a case report.
BACKGROUND
Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and had a cardiac arrest.
METHODS
A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.
CONCLUSIONS
Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
Background
Preoperative antibiotic prophylaxis has become a standard practice, in patients who will have an artificial implant or foreign body implanted as part of the procedure [1]. Vancomycin is one such antibiotic that is used for both prevention and treatment of infections caused by gram-positive bacteria predominantly staphylococcal infections, which is commonly encountered in orthopedic practice. However the use of intravenous vancomycin demands extreme caution, as accidental rapid infusion can precipitate Red Man Syndrome (RMS) that can be life-threatening, if not identified and managed aptly. In this case report, we aim to highlight this rare and yet dreadful adverse effect of vancomycin, that can occur in daily clinical practice.
Case presentation
We recount of a 9-year-old Asian girl diagnosed with Ewing’s sarcoma of left distal tibia. She had received six cycles of chemotherapy that had reduced the size of periosteal lesion compared to few months back. So she was planned for wide resection of the tumor along with reconstruction of her leg. To prevent the risks of implant associated infection, it was decided that the bone cement used during surgery would be impregnated with vancomycin. Following a routine pre-anesthetic assessment, she was cleared for surgery.
A night before the surgery at around 10 pm, an order of prophylactic intravenous vancomycin 500 milligram (mg) in 100 milliliters (mls) of 0.9% normal saline (NS) over 1 hour was carried out in the orthopedic ward. However the drug was accidently infused in about 5 minutes. Soon the patient was restless, complained of epigastric discomfort along with suffocation and feeling of tightness in her chest and neck. There was visible flushing of her face. Within a matter of seconds, she was dyspneic with oxygen saturation falling to 40% along with drop in blood pressure to 40/20 millimeters of mercury (mm Hg). Suddenly her respiration ceased and carotid pulse was impalpable. Immediately chest compression was initiated along with bag and mask ventilation. 0.9% NS was infused rapidly. The patient’s trachea was intubated and ventilation continued. There was return of spontaneous circulation (ROSC) after a minute of chest compressions. Following ROSC, her heart rate was 140 beats per minute in sinus rhythm, oxygen saturation of 99 % with oxygen and blood pressure of 120/90 mm of Hg with Glasgow coma scale (GCS) of E4M5Vt. She was given an injection of pheniramine 10 mg and hydrocortisone 50 mg intravenously. On auscultation of chest, there was decreased air entry bilaterally along with expiratory wheeze that resolved with salbutamol nebulization. She was shifted to Intensive care unit (ICU) where respiration was controlled by mechanical ventilation overnight under sedation. A chest x-ray done was normal. Overnight there were no issues to be addressed and was planned for gradual tapering of sedation. In the morning, she gradually gained full consciousness with normal arterial blood gas analysis and blood reports. The patient’s trachea was extubated following a successful spontaneous breathing trial with T-piece. She was discharged from ICU in the evening with resumption of normal feeding and discharged from the hospital a day after.
The child was admitted again three weeks later and underwent the contemplated procedure uneventfully.
Discussion
The prescription of antibiotics is inevitable and with it its unwanted adverse effects. Vancomycin use brings to the table the risks of two hypersensitivity reaction namely anaphylaxis and Red Man Syndrome [2, 3]. While it is a daunting task to differentiate anaphylaxis from RMS clinically, the latter is believed to be related to the rate of intravenous infusion and it being the more common reaction between the two [3]. RMS, an anaphylactoid reaction, owes it effects to histamine release following mast cell degranulation whereas anaphylaxis is Ig-E mediated. Role of plasma tryptase to differentiate the two reaction is doubtful. RMS is seen in 3.7 to 47% in infected patients and up to 90% in healthy volunteers [3]. Patients younger than the age of 40, particularly children are vulnerable to its severe form [4]. In children receiving vancomycin, the prevalence of RMS is 14% [5]. The dictum with vancomycin infusion has always been to do so slowly and carefully. However, in our case inadvertent rapid infusion of vancomycin lead to a life threatening situation.
RMS presents with generalized flushing, pruritus and erythematous rash affecting the upper body, neck, and face. In its severe form, dyspnoea, chest discomfort and hypotension can occur. Hypotension without the appearance of a rash has also been reported [6]. RMS is rarely life-threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [6–8]. Our patient had brief flushing of her face with respiratory distress and hypotension which eventually progressed to cardiac-respiratory arrest. We did not look for rashes as cardiopulmonary resuscitation was started immediately and by the time the patient became stable, no flushing and rashes were noted.
RMS is a consequence of histamine release from mast cells and basophils located in the skin, lung, gastrointestinal tract, myocardium, and vascular system [3]. Histamine release occurs as a result of interaction of vancomycin with Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2), a G-protein-coupled receptor mediating Ig-E independent mast cell degranulation [9, 10]. The fact that pretreatment with antihistamines has shown to reduce the effects of RMS further supports the histamine mediated mechanism [11]. The severity of reaction is proportional to the amount of histamine release [3]. Signs and symptoms may occur after 4–10 minutes of intravenous infusion or after its completion and even further delayed presentation have been reported [12].
Although commonly encountered with parenteral use of vancomycin, RMS has also been reported, when used in oral form [13], powder form [13] and vancomycin loaded bone cement [14]. Other antibiotics such as ciprofloxacin, amphotericin B, rifampin, and teicoplanin are also potentially linked with RMS [15]. The concomitant use of opioid analgesics, muscle relaxants, contrast dye with vancomycin seems to augment the effects of RMS [12]. Our patient did not receive any such medications and a link between past use of chemotherapy and vancomycin could not be established.
Vigilance during vancomycin infusion can identify any untoward reaction and warrant intervention. It is recommended to administer intravenous vancomycin over one to two hours duration preferably using volumetric pump with infusion rate not exceeding 10 mg/min [6] Pretreatment with antihistamines may reduce the incidence and severity of RMS [6, 11]. The infusion should be stopped right away when features of RMS is noticed and antihistamines prescribed to treat them. Corticosteroids can come to rescue in refractory cases. Occasionally, there may be the need to maintain circulation with intravenous fluids and ensure adequate oxygenation to stabilize the hemodynamics. Vancomycin desensitization is suggested in patients where the classical treatment modality is unable to stop RMS and there is the absolute need to continue vancomycin [3].
Conclusion
Vancomycin use in perioperative period is ever flourishing. This report sheds light to a rare adverse effect that can be encountered with its use. However awareness among healthcare practitioners and a well-designed protocol about the vancomycin infusion will prove worthwhile.
Abbreviations
GCSGlasgow coma scale
ICUIntensive care unit
MgMilligram
MlMilliliters
Mm of HgMillimeters of mercury
MRGPRX2Mas-related G-protein-coupled receptor X2
NSNormal saline
ROSCReturn of spontaneous circulation
RMSRed Man Syndrome
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contribution
SK was directly involved in management of the patient. He collected relevant information, designed, drafted, edited the report. SR was also involved in patient management and revised the report. Both authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | VANCOMYCIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33593409 | 19,721,726 | 2021-02-16 |
What was the administration route of drug 'VANCOMYCIN HYDROCHLORIDE'? | Vancomycin induced cardiac arrest: a case report.
BACKGROUND
Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and had a cardiac arrest.
METHODS
A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.
CONCLUSIONS
Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
Background
Preoperative antibiotic prophylaxis has become a standard practice, in patients who will have an artificial implant or foreign body implanted as part of the procedure [1]. Vancomycin is one such antibiotic that is used for both prevention and treatment of infections caused by gram-positive bacteria predominantly staphylococcal infections, which is commonly encountered in orthopedic practice. However the use of intravenous vancomycin demands extreme caution, as accidental rapid infusion can precipitate Red Man Syndrome (RMS) that can be life-threatening, if not identified and managed aptly. In this case report, we aim to highlight this rare and yet dreadful adverse effect of vancomycin, that can occur in daily clinical practice.
Case presentation
We recount of a 9-year-old Asian girl diagnosed with Ewing’s sarcoma of left distal tibia. She had received six cycles of chemotherapy that had reduced the size of periosteal lesion compared to few months back. So she was planned for wide resection of the tumor along with reconstruction of her leg. To prevent the risks of implant associated infection, it was decided that the bone cement used during surgery would be impregnated with vancomycin. Following a routine pre-anesthetic assessment, she was cleared for surgery.
A night before the surgery at around 10 pm, an order of prophylactic intravenous vancomycin 500 milligram (mg) in 100 milliliters (mls) of 0.9% normal saline (NS) over 1 hour was carried out in the orthopedic ward. However the drug was accidently infused in about 5 minutes. Soon the patient was restless, complained of epigastric discomfort along with suffocation and feeling of tightness in her chest and neck. There was visible flushing of her face. Within a matter of seconds, she was dyspneic with oxygen saturation falling to 40% along with drop in blood pressure to 40/20 millimeters of mercury (mm Hg). Suddenly her respiration ceased and carotid pulse was impalpable. Immediately chest compression was initiated along with bag and mask ventilation. 0.9% NS was infused rapidly. The patient’s trachea was intubated and ventilation continued. There was return of spontaneous circulation (ROSC) after a minute of chest compressions. Following ROSC, her heart rate was 140 beats per minute in sinus rhythm, oxygen saturation of 99 % with oxygen and blood pressure of 120/90 mm of Hg with Glasgow coma scale (GCS) of E4M5Vt. She was given an injection of pheniramine 10 mg and hydrocortisone 50 mg intravenously. On auscultation of chest, there was decreased air entry bilaterally along with expiratory wheeze that resolved with salbutamol nebulization. She was shifted to Intensive care unit (ICU) where respiration was controlled by mechanical ventilation overnight under sedation. A chest x-ray done was normal. Overnight there were no issues to be addressed and was planned for gradual tapering of sedation. In the morning, she gradually gained full consciousness with normal arterial blood gas analysis and blood reports. The patient’s trachea was extubated following a successful spontaneous breathing trial with T-piece. She was discharged from ICU in the evening with resumption of normal feeding and discharged from the hospital a day after.
The child was admitted again three weeks later and underwent the contemplated procedure uneventfully.
Discussion
The prescription of antibiotics is inevitable and with it its unwanted adverse effects. Vancomycin use brings to the table the risks of two hypersensitivity reaction namely anaphylaxis and Red Man Syndrome [2, 3]. While it is a daunting task to differentiate anaphylaxis from RMS clinically, the latter is believed to be related to the rate of intravenous infusion and it being the more common reaction between the two [3]. RMS, an anaphylactoid reaction, owes it effects to histamine release following mast cell degranulation whereas anaphylaxis is Ig-E mediated. Role of plasma tryptase to differentiate the two reaction is doubtful. RMS is seen in 3.7 to 47% in infected patients and up to 90% in healthy volunteers [3]. Patients younger than the age of 40, particularly children are vulnerable to its severe form [4]. In children receiving vancomycin, the prevalence of RMS is 14% [5]. The dictum with vancomycin infusion has always been to do so slowly and carefully. However, in our case inadvertent rapid infusion of vancomycin lead to a life threatening situation.
RMS presents with generalized flushing, pruritus and erythematous rash affecting the upper body, neck, and face. In its severe form, dyspnoea, chest discomfort and hypotension can occur. Hypotension without the appearance of a rash has also been reported [6]. RMS is rarely life-threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [6–8]. Our patient had brief flushing of her face with respiratory distress and hypotension which eventually progressed to cardiac-respiratory arrest. We did not look for rashes as cardiopulmonary resuscitation was started immediately and by the time the patient became stable, no flushing and rashes were noted.
RMS is a consequence of histamine release from mast cells and basophils located in the skin, lung, gastrointestinal tract, myocardium, and vascular system [3]. Histamine release occurs as a result of interaction of vancomycin with Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2), a G-protein-coupled receptor mediating Ig-E independent mast cell degranulation [9, 10]. The fact that pretreatment with antihistamines has shown to reduce the effects of RMS further supports the histamine mediated mechanism [11]. The severity of reaction is proportional to the amount of histamine release [3]. Signs and symptoms may occur after 4–10 minutes of intravenous infusion or after its completion and even further delayed presentation have been reported [12].
Although commonly encountered with parenteral use of vancomycin, RMS has also been reported, when used in oral form [13], powder form [13] and vancomycin loaded bone cement [14]. Other antibiotics such as ciprofloxacin, amphotericin B, rifampin, and teicoplanin are also potentially linked with RMS [15]. The concomitant use of opioid analgesics, muscle relaxants, contrast dye with vancomycin seems to augment the effects of RMS [12]. Our patient did not receive any such medications and a link between past use of chemotherapy and vancomycin could not be established.
Vigilance during vancomycin infusion can identify any untoward reaction and warrant intervention. It is recommended to administer intravenous vancomycin over one to two hours duration preferably using volumetric pump with infusion rate not exceeding 10 mg/min [6] Pretreatment with antihistamines may reduce the incidence and severity of RMS [6, 11]. The infusion should be stopped right away when features of RMS is noticed and antihistamines prescribed to treat them. Corticosteroids can come to rescue in refractory cases. Occasionally, there may be the need to maintain circulation with intravenous fluids and ensure adequate oxygenation to stabilize the hemodynamics. Vancomycin desensitization is suggested in patients where the classical treatment modality is unable to stop RMS and there is the absolute need to continue vancomycin [3].
Conclusion
Vancomycin use in perioperative period is ever flourishing. This report sheds light to a rare adverse effect that can be encountered with its use. However awareness among healthcare practitioners and a well-designed protocol about the vancomycin infusion will prove worthwhile.
Abbreviations
GCSGlasgow coma scale
ICUIntensive care unit
MgMilligram
MlMilliliters
Mm of HgMillimeters of mercury
MRGPRX2Mas-related G-protein-coupled receptor X2
NSNormal saline
ROSCReturn of spontaneous circulation
RMSRed Man Syndrome
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contribution
SK was directly involved in management of the patient. He collected relevant information, designed, drafted, edited the report. SR was also involved in patient management and revised the report. Both authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33593409 | 19,721,726 | 2021-02-16 |
What was the administration route of drug 'VANCOMYCIN'? | Vancomycin induced cardiac arrest: a case report.
BACKGROUND
Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and had a cardiac arrest.
METHODS
A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.
CONCLUSIONS
Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
Background
Preoperative antibiotic prophylaxis has become a standard practice, in patients who will have an artificial implant or foreign body implanted as part of the procedure [1]. Vancomycin is one such antibiotic that is used for both prevention and treatment of infections caused by gram-positive bacteria predominantly staphylococcal infections, which is commonly encountered in orthopedic practice. However the use of intravenous vancomycin demands extreme caution, as accidental rapid infusion can precipitate Red Man Syndrome (RMS) that can be life-threatening, if not identified and managed aptly. In this case report, we aim to highlight this rare and yet dreadful adverse effect of vancomycin, that can occur in daily clinical practice.
Case presentation
We recount of a 9-year-old Asian girl diagnosed with Ewing’s sarcoma of left distal tibia. She had received six cycles of chemotherapy that had reduced the size of periosteal lesion compared to few months back. So she was planned for wide resection of the tumor along with reconstruction of her leg. To prevent the risks of implant associated infection, it was decided that the bone cement used during surgery would be impregnated with vancomycin. Following a routine pre-anesthetic assessment, she was cleared for surgery.
A night before the surgery at around 10 pm, an order of prophylactic intravenous vancomycin 500 milligram (mg) in 100 milliliters (mls) of 0.9% normal saline (NS) over 1 hour was carried out in the orthopedic ward. However the drug was accidently infused in about 5 minutes. Soon the patient was restless, complained of epigastric discomfort along with suffocation and feeling of tightness in her chest and neck. There was visible flushing of her face. Within a matter of seconds, she was dyspneic with oxygen saturation falling to 40% along with drop in blood pressure to 40/20 millimeters of mercury (mm Hg). Suddenly her respiration ceased and carotid pulse was impalpable. Immediately chest compression was initiated along with bag and mask ventilation. 0.9% NS was infused rapidly. The patient’s trachea was intubated and ventilation continued. There was return of spontaneous circulation (ROSC) after a minute of chest compressions. Following ROSC, her heart rate was 140 beats per minute in sinus rhythm, oxygen saturation of 99 % with oxygen and blood pressure of 120/90 mm of Hg with Glasgow coma scale (GCS) of E4M5Vt. She was given an injection of pheniramine 10 mg and hydrocortisone 50 mg intravenously. On auscultation of chest, there was decreased air entry bilaterally along with expiratory wheeze that resolved with salbutamol nebulization. She was shifted to Intensive care unit (ICU) where respiration was controlled by mechanical ventilation overnight under sedation. A chest x-ray done was normal. Overnight there were no issues to be addressed and was planned for gradual tapering of sedation. In the morning, she gradually gained full consciousness with normal arterial blood gas analysis and blood reports. The patient’s trachea was extubated following a successful spontaneous breathing trial with T-piece. She was discharged from ICU in the evening with resumption of normal feeding and discharged from the hospital a day after.
The child was admitted again three weeks later and underwent the contemplated procedure uneventfully.
Discussion
The prescription of antibiotics is inevitable and with it its unwanted adverse effects. Vancomycin use brings to the table the risks of two hypersensitivity reaction namely anaphylaxis and Red Man Syndrome [2, 3]. While it is a daunting task to differentiate anaphylaxis from RMS clinically, the latter is believed to be related to the rate of intravenous infusion and it being the more common reaction between the two [3]. RMS, an anaphylactoid reaction, owes it effects to histamine release following mast cell degranulation whereas anaphylaxis is Ig-E mediated. Role of plasma tryptase to differentiate the two reaction is doubtful. RMS is seen in 3.7 to 47% in infected patients and up to 90% in healthy volunteers [3]. Patients younger than the age of 40, particularly children are vulnerable to its severe form [4]. In children receiving vancomycin, the prevalence of RMS is 14% [5]. The dictum with vancomycin infusion has always been to do so slowly and carefully. However, in our case inadvertent rapid infusion of vancomycin lead to a life threatening situation.
RMS presents with generalized flushing, pruritus and erythematous rash affecting the upper body, neck, and face. In its severe form, dyspnoea, chest discomfort and hypotension can occur. Hypotension without the appearance of a rash has also been reported [6]. RMS is rarely life-threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [6–8]. Our patient had brief flushing of her face with respiratory distress and hypotension which eventually progressed to cardiac-respiratory arrest. We did not look for rashes as cardiopulmonary resuscitation was started immediately and by the time the patient became stable, no flushing and rashes were noted.
RMS is a consequence of histamine release from mast cells and basophils located in the skin, lung, gastrointestinal tract, myocardium, and vascular system [3]. Histamine release occurs as a result of interaction of vancomycin with Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2), a G-protein-coupled receptor mediating Ig-E independent mast cell degranulation [9, 10]. The fact that pretreatment with antihistamines has shown to reduce the effects of RMS further supports the histamine mediated mechanism [11]. The severity of reaction is proportional to the amount of histamine release [3]. Signs and symptoms may occur after 4–10 minutes of intravenous infusion or after its completion and even further delayed presentation have been reported [12].
Although commonly encountered with parenteral use of vancomycin, RMS has also been reported, when used in oral form [13], powder form [13] and vancomycin loaded bone cement [14]. Other antibiotics such as ciprofloxacin, amphotericin B, rifampin, and teicoplanin are also potentially linked with RMS [15]. The concomitant use of opioid analgesics, muscle relaxants, contrast dye with vancomycin seems to augment the effects of RMS [12]. Our patient did not receive any such medications and a link between past use of chemotherapy and vancomycin could not be established.
Vigilance during vancomycin infusion can identify any untoward reaction and warrant intervention. It is recommended to administer intravenous vancomycin over one to two hours duration preferably using volumetric pump with infusion rate not exceeding 10 mg/min [6] Pretreatment with antihistamines may reduce the incidence and severity of RMS [6, 11]. The infusion should be stopped right away when features of RMS is noticed and antihistamines prescribed to treat them. Corticosteroids can come to rescue in refractory cases. Occasionally, there may be the need to maintain circulation with intravenous fluids and ensure adequate oxygenation to stabilize the hemodynamics. Vancomycin desensitization is suggested in patients where the classical treatment modality is unable to stop RMS and there is the absolute need to continue vancomycin [3].
Conclusion
Vancomycin use in perioperative period is ever flourishing. This report sheds light to a rare adverse effect that can be encountered with its use. However awareness among healthcare practitioners and a well-designed protocol about the vancomycin infusion will prove worthwhile.
Abbreviations
GCSGlasgow coma scale
ICUIntensive care unit
MgMilligram
MlMilliliters
Mm of HgMillimeters of mercury
MRGPRX2Mas-related G-protein-coupled receptor X2
NSNormal saline
ROSCReturn of spontaneous circulation
RMSRed Man Syndrome
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contribution
SK was directly involved in management of the patient. He collected relevant information, designed, drafted, edited the report. SR was also involved in patient management and revised the report. Both authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33593409 | 18,972,960 | 2021-02-16 |
What was the outcome of reaction 'Cardiac arrest'? | Vancomycin induced cardiac arrest: a case report.
BACKGROUND
Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and had a cardiac arrest.
METHODS
A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.
CONCLUSIONS
Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
Background
Preoperative antibiotic prophylaxis has become a standard practice, in patients who will have an artificial implant or foreign body implanted as part of the procedure [1]. Vancomycin is one such antibiotic that is used for both prevention and treatment of infections caused by gram-positive bacteria predominantly staphylococcal infections, which is commonly encountered in orthopedic practice. However the use of intravenous vancomycin demands extreme caution, as accidental rapid infusion can precipitate Red Man Syndrome (RMS) that can be life-threatening, if not identified and managed aptly. In this case report, we aim to highlight this rare and yet dreadful adverse effect of vancomycin, that can occur in daily clinical practice.
Case presentation
We recount of a 9-year-old Asian girl diagnosed with Ewing’s sarcoma of left distal tibia. She had received six cycles of chemotherapy that had reduced the size of periosteal lesion compared to few months back. So she was planned for wide resection of the tumor along with reconstruction of her leg. To prevent the risks of implant associated infection, it was decided that the bone cement used during surgery would be impregnated with vancomycin. Following a routine pre-anesthetic assessment, she was cleared for surgery.
A night before the surgery at around 10 pm, an order of prophylactic intravenous vancomycin 500 milligram (mg) in 100 milliliters (mls) of 0.9% normal saline (NS) over 1 hour was carried out in the orthopedic ward. However the drug was accidently infused in about 5 minutes. Soon the patient was restless, complained of epigastric discomfort along with suffocation and feeling of tightness in her chest and neck. There was visible flushing of her face. Within a matter of seconds, she was dyspneic with oxygen saturation falling to 40% along with drop in blood pressure to 40/20 millimeters of mercury (mm Hg). Suddenly her respiration ceased and carotid pulse was impalpable. Immediately chest compression was initiated along with bag and mask ventilation. 0.9% NS was infused rapidly. The patient’s trachea was intubated and ventilation continued. There was return of spontaneous circulation (ROSC) after a minute of chest compressions. Following ROSC, her heart rate was 140 beats per minute in sinus rhythm, oxygen saturation of 99 % with oxygen and blood pressure of 120/90 mm of Hg with Glasgow coma scale (GCS) of E4M5Vt. She was given an injection of pheniramine 10 mg and hydrocortisone 50 mg intravenously. On auscultation of chest, there was decreased air entry bilaterally along with expiratory wheeze that resolved with salbutamol nebulization. She was shifted to Intensive care unit (ICU) where respiration was controlled by mechanical ventilation overnight under sedation. A chest x-ray done was normal. Overnight there were no issues to be addressed and was planned for gradual tapering of sedation. In the morning, she gradually gained full consciousness with normal arterial blood gas analysis and blood reports. The patient’s trachea was extubated following a successful spontaneous breathing trial with T-piece. She was discharged from ICU in the evening with resumption of normal feeding and discharged from the hospital a day after.
The child was admitted again three weeks later and underwent the contemplated procedure uneventfully.
Discussion
The prescription of antibiotics is inevitable and with it its unwanted adverse effects. Vancomycin use brings to the table the risks of two hypersensitivity reaction namely anaphylaxis and Red Man Syndrome [2, 3]. While it is a daunting task to differentiate anaphylaxis from RMS clinically, the latter is believed to be related to the rate of intravenous infusion and it being the more common reaction between the two [3]. RMS, an anaphylactoid reaction, owes it effects to histamine release following mast cell degranulation whereas anaphylaxis is Ig-E mediated. Role of plasma tryptase to differentiate the two reaction is doubtful. RMS is seen in 3.7 to 47% in infected patients and up to 90% in healthy volunteers [3]. Patients younger than the age of 40, particularly children are vulnerable to its severe form [4]. In children receiving vancomycin, the prevalence of RMS is 14% [5]. The dictum with vancomycin infusion has always been to do so slowly and carefully. However, in our case inadvertent rapid infusion of vancomycin lead to a life threatening situation.
RMS presents with generalized flushing, pruritus and erythematous rash affecting the upper body, neck, and face. In its severe form, dyspnoea, chest discomfort and hypotension can occur. Hypotension without the appearance of a rash has also been reported [6]. RMS is rarely life-threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [6–8]. Our patient had brief flushing of her face with respiratory distress and hypotension which eventually progressed to cardiac-respiratory arrest. We did not look for rashes as cardiopulmonary resuscitation was started immediately and by the time the patient became stable, no flushing and rashes were noted.
RMS is a consequence of histamine release from mast cells and basophils located in the skin, lung, gastrointestinal tract, myocardium, and vascular system [3]. Histamine release occurs as a result of interaction of vancomycin with Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2), a G-protein-coupled receptor mediating Ig-E independent mast cell degranulation [9, 10]. The fact that pretreatment with antihistamines has shown to reduce the effects of RMS further supports the histamine mediated mechanism [11]. The severity of reaction is proportional to the amount of histamine release [3]. Signs and symptoms may occur after 4–10 minutes of intravenous infusion or after its completion and even further delayed presentation have been reported [12].
Although commonly encountered with parenteral use of vancomycin, RMS has also been reported, when used in oral form [13], powder form [13] and vancomycin loaded bone cement [14]. Other antibiotics such as ciprofloxacin, amphotericin B, rifampin, and teicoplanin are also potentially linked with RMS [15]. The concomitant use of opioid analgesics, muscle relaxants, contrast dye with vancomycin seems to augment the effects of RMS [12]. Our patient did not receive any such medications and a link between past use of chemotherapy and vancomycin could not be established.
Vigilance during vancomycin infusion can identify any untoward reaction and warrant intervention. It is recommended to administer intravenous vancomycin over one to two hours duration preferably using volumetric pump with infusion rate not exceeding 10 mg/min [6] Pretreatment with antihistamines may reduce the incidence and severity of RMS [6, 11]. The infusion should be stopped right away when features of RMS is noticed and antihistamines prescribed to treat them. Corticosteroids can come to rescue in refractory cases. Occasionally, there may be the need to maintain circulation with intravenous fluids and ensure adequate oxygenation to stabilize the hemodynamics. Vancomycin desensitization is suggested in patients where the classical treatment modality is unable to stop RMS and there is the absolute need to continue vancomycin [3].
Conclusion
Vancomycin use in perioperative period is ever flourishing. This report sheds light to a rare adverse effect that can be encountered with its use. However awareness among healthcare practitioners and a well-designed protocol about the vancomycin infusion will prove worthwhile.
Abbreviations
GCSGlasgow coma scale
ICUIntensive care unit
MgMilligram
MlMilliliters
Mm of HgMillimeters of mercury
MRGPRX2Mas-related G-protein-coupled receptor X2
NSNormal saline
ROSCReturn of spontaneous circulation
RMSRed Man Syndrome
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contribution
SK was directly involved in management of the patient. He collected relevant information, designed, drafted, edited the report. SR was also involved in patient management and revised the report. Both authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33593409 | 18,972,960 | 2021-02-16 |
What was the outcome of reaction 'Cardio-respiratory arrest'? | Vancomycin induced cardiac arrest: a case report.
BACKGROUND
Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and had a cardiac arrest.
METHODS
A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.
CONCLUSIONS
Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
Background
Preoperative antibiotic prophylaxis has become a standard practice, in patients who will have an artificial implant or foreign body implanted as part of the procedure [1]. Vancomycin is one such antibiotic that is used for both prevention and treatment of infections caused by gram-positive bacteria predominantly staphylococcal infections, which is commonly encountered in orthopedic practice. However the use of intravenous vancomycin demands extreme caution, as accidental rapid infusion can precipitate Red Man Syndrome (RMS) that can be life-threatening, if not identified and managed aptly. In this case report, we aim to highlight this rare and yet dreadful adverse effect of vancomycin, that can occur in daily clinical practice.
Case presentation
We recount of a 9-year-old Asian girl diagnosed with Ewing’s sarcoma of left distal tibia. She had received six cycles of chemotherapy that had reduced the size of periosteal lesion compared to few months back. So she was planned for wide resection of the tumor along with reconstruction of her leg. To prevent the risks of implant associated infection, it was decided that the bone cement used during surgery would be impregnated with vancomycin. Following a routine pre-anesthetic assessment, she was cleared for surgery.
A night before the surgery at around 10 pm, an order of prophylactic intravenous vancomycin 500 milligram (mg) in 100 milliliters (mls) of 0.9% normal saline (NS) over 1 hour was carried out in the orthopedic ward. However the drug was accidently infused in about 5 minutes. Soon the patient was restless, complained of epigastric discomfort along with suffocation and feeling of tightness in her chest and neck. There was visible flushing of her face. Within a matter of seconds, she was dyspneic with oxygen saturation falling to 40% along with drop in blood pressure to 40/20 millimeters of mercury (mm Hg). Suddenly her respiration ceased and carotid pulse was impalpable. Immediately chest compression was initiated along with bag and mask ventilation. 0.9% NS was infused rapidly. The patient’s trachea was intubated and ventilation continued. There was return of spontaneous circulation (ROSC) after a minute of chest compressions. Following ROSC, her heart rate was 140 beats per minute in sinus rhythm, oxygen saturation of 99 % with oxygen and blood pressure of 120/90 mm of Hg with Glasgow coma scale (GCS) of E4M5Vt. She was given an injection of pheniramine 10 mg and hydrocortisone 50 mg intravenously. On auscultation of chest, there was decreased air entry bilaterally along with expiratory wheeze that resolved with salbutamol nebulization. She was shifted to Intensive care unit (ICU) where respiration was controlled by mechanical ventilation overnight under sedation. A chest x-ray done was normal. Overnight there were no issues to be addressed and was planned for gradual tapering of sedation. In the morning, she gradually gained full consciousness with normal arterial blood gas analysis and blood reports. The patient’s trachea was extubated following a successful spontaneous breathing trial with T-piece. She was discharged from ICU in the evening with resumption of normal feeding and discharged from the hospital a day after.
The child was admitted again three weeks later and underwent the contemplated procedure uneventfully.
Discussion
The prescription of antibiotics is inevitable and with it its unwanted adverse effects. Vancomycin use brings to the table the risks of two hypersensitivity reaction namely anaphylaxis and Red Man Syndrome [2, 3]. While it is a daunting task to differentiate anaphylaxis from RMS clinically, the latter is believed to be related to the rate of intravenous infusion and it being the more common reaction between the two [3]. RMS, an anaphylactoid reaction, owes it effects to histamine release following mast cell degranulation whereas anaphylaxis is Ig-E mediated. Role of plasma tryptase to differentiate the two reaction is doubtful. RMS is seen in 3.7 to 47% in infected patients and up to 90% in healthy volunteers [3]. Patients younger than the age of 40, particularly children are vulnerable to its severe form [4]. In children receiving vancomycin, the prevalence of RMS is 14% [5]. The dictum with vancomycin infusion has always been to do so slowly and carefully. However, in our case inadvertent rapid infusion of vancomycin lead to a life threatening situation.
RMS presents with generalized flushing, pruritus and erythematous rash affecting the upper body, neck, and face. In its severe form, dyspnoea, chest discomfort and hypotension can occur. Hypotension without the appearance of a rash has also been reported [6]. RMS is rarely life-threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [6–8]. Our patient had brief flushing of her face with respiratory distress and hypotension which eventually progressed to cardiac-respiratory arrest. We did not look for rashes as cardiopulmonary resuscitation was started immediately and by the time the patient became stable, no flushing and rashes were noted.
RMS is a consequence of histamine release from mast cells and basophils located in the skin, lung, gastrointestinal tract, myocardium, and vascular system [3]. Histamine release occurs as a result of interaction of vancomycin with Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2), a G-protein-coupled receptor mediating Ig-E independent mast cell degranulation [9, 10]. The fact that pretreatment with antihistamines has shown to reduce the effects of RMS further supports the histamine mediated mechanism [11]. The severity of reaction is proportional to the amount of histamine release [3]. Signs and symptoms may occur after 4–10 minutes of intravenous infusion or after its completion and even further delayed presentation have been reported [12].
Although commonly encountered with parenteral use of vancomycin, RMS has also been reported, when used in oral form [13], powder form [13] and vancomycin loaded bone cement [14]. Other antibiotics such as ciprofloxacin, amphotericin B, rifampin, and teicoplanin are also potentially linked with RMS [15]. The concomitant use of opioid analgesics, muscle relaxants, contrast dye with vancomycin seems to augment the effects of RMS [12]. Our patient did not receive any such medications and a link between past use of chemotherapy and vancomycin could not be established.
Vigilance during vancomycin infusion can identify any untoward reaction and warrant intervention. It is recommended to administer intravenous vancomycin over one to two hours duration preferably using volumetric pump with infusion rate not exceeding 10 mg/min [6] Pretreatment with antihistamines may reduce the incidence and severity of RMS [6, 11]. The infusion should be stopped right away when features of RMS is noticed and antihistamines prescribed to treat them. Corticosteroids can come to rescue in refractory cases. Occasionally, there may be the need to maintain circulation with intravenous fluids and ensure adequate oxygenation to stabilize the hemodynamics. Vancomycin desensitization is suggested in patients where the classical treatment modality is unable to stop RMS and there is the absolute need to continue vancomycin [3].
Conclusion
Vancomycin use in perioperative period is ever flourishing. This report sheds light to a rare adverse effect that can be encountered with its use. However awareness among healthcare practitioners and a well-designed protocol about the vancomycin infusion will prove worthwhile.
Abbreviations
GCSGlasgow coma scale
ICUIntensive care unit
MgMilligram
MlMilliliters
Mm of HgMillimeters of mercury
MRGPRX2Mas-related G-protein-coupled receptor X2
NSNormal saline
ROSCReturn of spontaneous circulation
RMSRed Man Syndrome
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contribution
SK was directly involved in management of the patient. He collected relevant information, designed, drafted, edited the report. SR was also involved in patient management and revised the report. Both authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33593409 | 19,721,726 | 2021-02-16 |
What was the outcome of reaction 'Depressed level of consciousness'? | Vancomycin induced cardiac arrest: a case report.
BACKGROUND
Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and had a cardiac arrest.
METHODS
A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.
CONCLUSIONS
Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
Background
Preoperative antibiotic prophylaxis has become a standard practice, in patients who will have an artificial implant or foreign body implanted as part of the procedure [1]. Vancomycin is one such antibiotic that is used for both prevention and treatment of infections caused by gram-positive bacteria predominantly staphylococcal infections, which is commonly encountered in orthopedic practice. However the use of intravenous vancomycin demands extreme caution, as accidental rapid infusion can precipitate Red Man Syndrome (RMS) that can be life-threatening, if not identified and managed aptly. In this case report, we aim to highlight this rare and yet dreadful adverse effect of vancomycin, that can occur in daily clinical practice.
Case presentation
We recount of a 9-year-old Asian girl diagnosed with Ewing’s sarcoma of left distal tibia. She had received six cycles of chemotherapy that had reduced the size of periosteal lesion compared to few months back. So she was planned for wide resection of the tumor along with reconstruction of her leg. To prevent the risks of implant associated infection, it was decided that the bone cement used during surgery would be impregnated with vancomycin. Following a routine pre-anesthetic assessment, she was cleared for surgery.
A night before the surgery at around 10 pm, an order of prophylactic intravenous vancomycin 500 milligram (mg) in 100 milliliters (mls) of 0.9% normal saline (NS) over 1 hour was carried out in the orthopedic ward. However the drug was accidently infused in about 5 minutes. Soon the patient was restless, complained of epigastric discomfort along with suffocation and feeling of tightness in her chest and neck. There was visible flushing of her face. Within a matter of seconds, she was dyspneic with oxygen saturation falling to 40% along with drop in blood pressure to 40/20 millimeters of mercury (mm Hg). Suddenly her respiration ceased and carotid pulse was impalpable. Immediately chest compression was initiated along with bag and mask ventilation. 0.9% NS was infused rapidly. The patient’s trachea was intubated and ventilation continued. There was return of spontaneous circulation (ROSC) after a minute of chest compressions. Following ROSC, her heart rate was 140 beats per minute in sinus rhythm, oxygen saturation of 99 % with oxygen and blood pressure of 120/90 mm of Hg with Glasgow coma scale (GCS) of E4M5Vt. She was given an injection of pheniramine 10 mg and hydrocortisone 50 mg intravenously. On auscultation of chest, there was decreased air entry bilaterally along with expiratory wheeze that resolved with salbutamol nebulization. She was shifted to Intensive care unit (ICU) where respiration was controlled by mechanical ventilation overnight under sedation. A chest x-ray done was normal. Overnight there were no issues to be addressed and was planned for gradual tapering of sedation. In the morning, she gradually gained full consciousness with normal arterial blood gas analysis and blood reports. The patient’s trachea was extubated following a successful spontaneous breathing trial with T-piece. She was discharged from ICU in the evening with resumption of normal feeding and discharged from the hospital a day after.
The child was admitted again three weeks later and underwent the contemplated procedure uneventfully.
Discussion
The prescription of antibiotics is inevitable and with it its unwanted adverse effects. Vancomycin use brings to the table the risks of two hypersensitivity reaction namely anaphylaxis and Red Man Syndrome [2, 3]. While it is a daunting task to differentiate anaphylaxis from RMS clinically, the latter is believed to be related to the rate of intravenous infusion and it being the more common reaction between the two [3]. RMS, an anaphylactoid reaction, owes it effects to histamine release following mast cell degranulation whereas anaphylaxis is Ig-E mediated. Role of plasma tryptase to differentiate the two reaction is doubtful. RMS is seen in 3.7 to 47% in infected patients and up to 90% in healthy volunteers [3]. Patients younger than the age of 40, particularly children are vulnerable to its severe form [4]. In children receiving vancomycin, the prevalence of RMS is 14% [5]. The dictum with vancomycin infusion has always been to do so slowly and carefully. However, in our case inadvertent rapid infusion of vancomycin lead to a life threatening situation.
RMS presents with generalized flushing, pruritus and erythematous rash affecting the upper body, neck, and face. In its severe form, dyspnoea, chest discomfort and hypotension can occur. Hypotension without the appearance of a rash has also been reported [6]. RMS is rarely life-threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [6–8]. Our patient had brief flushing of her face with respiratory distress and hypotension which eventually progressed to cardiac-respiratory arrest. We did not look for rashes as cardiopulmonary resuscitation was started immediately and by the time the patient became stable, no flushing and rashes were noted.
RMS is a consequence of histamine release from mast cells and basophils located in the skin, lung, gastrointestinal tract, myocardium, and vascular system [3]. Histamine release occurs as a result of interaction of vancomycin with Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2), a G-protein-coupled receptor mediating Ig-E independent mast cell degranulation [9, 10]. The fact that pretreatment with antihistamines has shown to reduce the effects of RMS further supports the histamine mediated mechanism [11]. The severity of reaction is proportional to the amount of histamine release [3]. Signs and symptoms may occur after 4–10 minutes of intravenous infusion or after its completion and even further delayed presentation have been reported [12].
Although commonly encountered with parenteral use of vancomycin, RMS has also been reported, when used in oral form [13], powder form [13] and vancomycin loaded bone cement [14]. Other antibiotics such as ciprofloxacin, amphotericin B, rifampin, and teicoplanin are also potentially linked with RMS [15]. The concomitant use of opioid analgesics, muscle relaxants, contrast dye with vancomycin seems to augment the effects of RMS [12]. Our patient did not receive any such medications and a link between past use of chemotherapy and vancomycin could not be established.
Vigilance during vancomycin infusion can identify any untoward reaction and warrant intervention. It is recommended to administer intravenous vancomycin over one to two hours duration preferably using volumetric pump with infusion rate not exceeding 10 mg/min [6] Pretreatment with antihistamines may reduce the incidence and severity of RMS [6, 11]. The infusion should be stopped right away when features of RMS is noticed and antihistamines prescribed to treat them. Corticosteroids can come to rescue in refractory cases. Occasionally, there may be the need to maintain circulation with intravenous fluids and ensure adequate oxygenation to stabilize the hemodynamics. Vancomycin desensitization is suggested in patients where the classical treatment modality is unable to stop RMS and there is the absolute need to continue vancomycin [3].
Conclusion
Vancomycin use in perioperative period is ever flourishing. This report sheds light to a rare adverse effect that can be encountered with its use. However awareness among healthcare practitioners and a well-designed protocol about the vancomycin infusion will prove worthwhile.
Abbreviations
GCSGlasgow coma scale
ICUIntensive care unit
MgMilligram
MlMilliliters
Mm of HgMillimeters of mercury
MRGPRX2Mas-related G-protein-coupled receptor X2
NSNormal saline
ROSCReturn of spontaneous circulation
RMSRed Man Syndrome
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contribution
SK was directly involved in management of the patient. He collected relevant information, designed, drafted, edited the report. SR was also involved in patient management and revised the report. Both authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33593409 | 19,721,726 | 2021-02-16 |
What was the outcome of reaction 'Incorrect drug administration rate'? | Vancomycin induced cardiac arrest: a case report.
BACKGROUND
Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and had a cardiac arrest.
METHODS
A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.
CONCLUSIONS
Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
Background
Preoperative antibiotic prophylaxis has become a standard practice, in patients who will have an artificial implant or foreign body implanted as part of the procedure [1]. Vancomycin is one such antibiotic that is used for both prevention and treatment of infections caused by gram-positive bacteria predominantly staphylococcal infections, which is commonly encountered in orthopedic practice. However the use of intravenous vancomycin demands extreme caution, as accidental rapid infusion can precipitate Red Man Syndrome (RMS) that can be life-threatening, if not identified and managed aptly. In this case report, we aim to highlight this rare and yet dreadful adverse effect of vancomycin, that can occur in daily clinical practice.
Case presentation
We recount of a 9-year-old Asian girl diagnosed with Ewing’s sarcoma of left distal tibia. She had received six cycles of chemotherapy that had reduced the size of periosteal lesion compared to few months back. So she was planned for wide resection of the tumor along with reconstruction of her leg. To prevent the risks of implant associated infection, it was decided that the bone cement used during surgery would be impregnated with vancomycin. Following a routine pre-anesthetic assessment, she was cleared for surgery.
A night before the surgery at around 10 pm, an order of prophylactic intravenous vancomycin 500 milligram (mg) in 100 milliliters (mls) of 0.9% normal saline (NS) over 1 hour was carried out in the orthopedic ward. However the drug was accidently infused in about 5 minutes. Soon the patient was restless, complained of epigastric discomfort along with suffocation and feeling of tightness in her chest and neck. There was visible flushing of her face. Within a matter of seconds, she was dyspneic with oxygen saturation falling to 40% along with drop in blood pressure to 40/20 millimeters of mercury (mm Hg). Suddenly her respiration ceased and carotid pulse was impalpable. Immediately chest compression was initiated along with bag and mask ventilation. 0.9% NS was infused rapidly. The patient’s trachea was intubated and ventilation continued. There was return of spontaneous circulation (ROSC) after a minute of chest compressions. Following ROSC, her heart rate was 140 beats per minute in sinus rhythm, oxygen saturation of 99 % with oxygen and blood pressure of 120/90 mm of Hg with Glasgow coma scale (GCS) of E4M5Vt. She was given an injection of pheniramine 10 mg and hydrocortisone 50 mg intravenously. On auscultation of chest, there was decreased air entry bilaterally along with expiratory wheeze that resolved with salbutamol nebulization. She was shifted to Intensive care unit (ICU) where respiration was controlled by mechanical ventilation overnight under sedation. A chest x-ray done was normal. Overnight there were no issues to be addressed and was planned for gradual tapering of sedation. In the morning, she gradually gained full consciousness with normal arterial blood gas analysis and blood reports. The patient’s trachea was extubated following a successful spontaneous breathing trial with T-piece. She was discharged from ICU in the evening with resumption of normal feeding and discharged from the hospital a day after.
The child was admitted again three weeks later and underwent the contemplated procedure uneventfully.
Discussion
The prescription of antibiotics is inevitable and with it its unwanted adverse effects. Vancomycin use brings to the table the risks of two hypersensitivity reaction namely anaphylaxis and Red Man Syndrome [2, 3]. While it is a daunting task to differentiate anaphylaxis from RMS clinically, the latter is believed to be related to the rate of intravenous infusion and it being the more common reaction between the two [3]. RMS, an anaphylactoid reaction, owes it effects to histamine release following mast cell degranulation whereas anaphylaxis is Ig-E mediated. Role of plasma tryptase to differentiate the two reaction is doubtful. RMS is seen in 3.7 to 47% in infected patients and up to 90% in healthy volunteers [3]. Patients younger than the age of 40, particularly children are vulnerable to its severe form [4]. In children receiving vancomycin, the prevalence of RMS is 14% [5]. The dictum with vancomycin infusion has always been to do so slowly and carefully. However, in our case inadvertent rapid infusion of vancomycin lead to a life threatening situation.
RMS presents with generalized flushing, pruritus and erythematous rash affecting the upper body, neck, and face. In its severe form, dyspnoea, chest discomfort and hypotension can occur. Hypotension without the appearance of a rash has also been reported [6]. RMS is rarely life-threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [6–8]. Our patient had brief flushing of her face with respiratory distress and hypotension which eventually progressed to cardiac-respiratory arrest. We did not look for rashes as cardiopulmonary resuscitation was started immediately and by the time the patient became stable, no flushing and rashes were noted.
RMS is a consequence of histamine release from mast cells and basophils located in the skin, lung, gastrointestinal tract, myocardium, and vascular system [3]. Histamine release occurs as a result of interaction of vancomycin with Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2), a G-protein-coupled receptor mediating Ig-E independent mast cell degranulation [9, 10]. The fact that pretreatment with antihistamines has shown to reduce the effects of RMS further supports the histamine mediated mechanism [11]. The severity of reaction is proportional to the amount of histamine release [3]. Signs and symptoms may occur after 4–10 minutes of intravenous infusion or after its completion and even further delayed presentation have been reported [12].
Although commonly encountered with parenteral use of vancomycin, RMS has also been reported, when used in oral form [13], powder form [13] and vancomycin loaded bone cement [14]. Other antibiotics such as ciprofloxacin, amphotericin B, rifampin, and teicoplanin are also potentially linked with RMS [15]. The concomitant use of opioid analgesics, muscle relaxants, contrast dye with vancomycin seems to augment the effects of RMS [12]. Our patient did not receive any such medications and a link between past use of chemotherapy and vancomycin could not be established.
Vigilance during vancomycin infusion can identify any untoward reaction and warrant intervention. It is recommended to administer intravenous vancomycin over one to two hours duration preferably using volumetric pump with infusion rate not exceeding 10 mg/min [6] Pretreatment with antihistamines may reduce the incidence and severity of RMS [6, 11]. The infusion should be stopped right away when features of RMS is noticed and antihistamines prescribed to treat them. Corticosteroids can come to rescue in refractory cases. Occasionally, there may be the need to maintain circulation with intravenous fluids and ensure adequate oxygenation to stabilize the hemodynamics. Vancomycin desensitization is suggested in patients where the classical treatment modality is unable to stop RMS and there is the absolute need to continue vancomycin [3].
Conclusion
Vancomycin use in perioperative period is ever flourishing. This report sheds light to a rare adverse effect that can be encountered with its use. However awareness among healthcare practitioners and a well-designed protocol about the vancomycin infusion will prove worthwhile.
Abbreviations
GCSGlasgow coma scale
ICUIntensive care unit
MgMilligram
MlMilliliters
Mm of HgMillimeters of mercury
MRGPRX2Mas-related G-protein-coupled receptor X2
NSNormal saline
ROSCReturn of spontaneous circulation
RMSRed Man Syndrome
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contribution
SK was directly involved in management of the patient. He collected relevant information, designed, drafted, edited the report. SR was also involved in patient management and revised the report. Both authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33593409 | 19,721,726 | 2021-02-16 |
What was the outcome of reaction 'Red man syndrome'? | Vancomycin induced cardiac arrest: a case report.
BACKGROUND
Rapid intravenous administration of vancomycin may manifest with histaminergic responses with clinical features ranging from mild rashes, pruritus and even shock. This case reports of a child, who was accidentally given intravenous vancomycin within minutes and had a cardiac arrest.
METHODS
A 9-year-old Asian girl who was scheduled for a limb salvage surgery, received vancomycin preoperatively. As a result of rapid infusion of the drug, the patient developed flushing, pruritus and had respiratory distress with hypotension leading to asystole. However, prompt detection and immediate cardiopulmonary resuscitation revived the patient in time following which sound recovery ensued. We recognised inadvertent brisk infusion of vancomycin as the culprit with strong suspicion of Red Man Syndrome.
CONCLUSIONS
Red Man Syndrome, though rarely encountered, can always be life threatening. With a surge in the use of vancomycin, adverse effects associated with its use also rises. So a comprehensive knowledge regarding its rationale use, adverse effects and its prompt management in personnel prescribing it, can be life saving.
Background
Preoperative antibiotic prophylaxis has become a standard practice, in patients who will have an artificial implant or foreign body implanted as part of the procedure [1]. Vancomycin is one such antibiotic that is used for both prevention and treatment of infections caused by gram-positive bacteria predominantly staphylococcal infections, which is commonly encountered in orthopedic practice. However the use of intravenous vancomycin demands extreme caution, as accidental rapid infusion can precipitate Red Man Syndrome (RMS) that can be life-threatening, if not identified and managed aptly. In this case report, we aim to highlight this rare and yet dreadful adverse effect of vancomycin, that can occur in daily clinical practice.
Case presentation
We recount of a 9-year-old Asian girl diagnosed with Ewing’s sarcoma of left distal tibia. She had received six cycles of chemotherapy that had reduced the size of periosteal lesion compared to few months back. So she was planned for wide resection of the tumor along with reconstruction of her leg. To prevent the risks of implant associated infection, it was decided that the bone cement used during surgery would be impregnated with vancomycin. Following a routine pre-anesthetic assessment, she was cleared for surgery.
A night before the surgery at around 10 pm, an order of prophylactic intravenous vancomycin 500 milligram (mg) in 100 milliliters (mls) of 0.9% normal saline (NS) over 1 hour was carried out in the orthopedic ward. However the drug was accidently infused in about 5 minutes. Soon the patient was restless, complained of epigastric discomfort along with suffocation and feeling of tightness in her chest and neck. There was visible flushing of her face. Within a matter of seconds, she was dyspneic with oxygen saturation falling to 40% along with drop in blood pressure to 40/20 millimeters of mercury (mm Hg). Suddenly her respiration ceased and carotid pulse was impalpable. Immediately chest compression was initiated along with bag and mask ventilation. 0.9% NS was infused rapidly. The patient’s trachea was intubated and ventilation continued. There was return of spontaneous circulation (ROSC) after a minute of chest compressions. Following ROSC, her heart rate was 140 beats per minute in sinus rhythm, oxygen saturation of 99 % with oxygen and blood pressure of 120/90 mm of Hg with Glasgow coma scale (GCS) of E4M5Vt. She was given an injection of pheniramine 10 mg and hydrocortisone 50 mg intravenously. On auscultation of chest, there was decreased air entry bilaterally along with expiratory wheeze that resolved with salbutamol nebulization. She was shifted to Intensive care unit (ICU) where respiration was controlled by mechanical ventilation overnight under sedation. A chest x-ray done was normal. Overnight there were no issues to be addressed and was planned for gradual tapering of sedation. In the morning, she gradually gained full consciousness with normal arterial blood gas analysis and blood reports. The patient’s trachea was extubated following a successful spontaneous breathing trial with T-piece. She was discharged from ICU in the evening with resumption of normal feeding and discharged from the hospital a day after.
The child was admitted again three weeks later and underwent the contemplated procedure uneventfully.
Discussion
The prescription of antibiotics is inevitable and with it its unwanted adverse effects. Vancomycin use brings to the table the risks of two hypersensitivity reaction namely anaphylaxis and Red Man Syndrome [2, 3]. While it is a daunting task to differentiate anaphylaxis from RMS clinically, the latter is believed to be related to the rate of intravenous infusion and it being the more common reaction between the two [3]. RMS, an anaphylactoid reaction, owes it effects to histamine release following mast cell degranulation whereas anaphylaxis is Ig-E mediated. Role of plasma tryptase to differentiate the two reaction is doubtful. RMS is seen in 3.7 to 47% in infected patients and up to 90% in healthy volunteers [3]. Patients younger than the age of 40, particularly children are vulnerable to its severe form [4]. In children receiving vancomycin, the prevalence of RMS is 14% [5]. The dictum with vancomycin infusion has always been to do so slowly and carefully. However, in our case inadvertent rapid infusion of vancomycin lead to a life threatening situation.
RMS presents with generalized flushing, pruritus and erythematous rash affecting the upper body, neck, and face. In its severe form, dyspnoea, chest discomfort and hypotension can occur. Hypotension without the appearance of a rash has also been reported [6]. RMS is rarely life-threatening, although severe cardiovascular toxicity and even cardiac arrest can occur [6–8]. Our patient had brief flushing of her face with respiratory distress and hypotension which eventually progressed to cardiac-respiratory arrest. We did not look for rashes as cardiopulmonary resuscitation was started immediately and by the time the patient became stable, no flushing and rashes were noted.
RMS is a consequence of histamine release from mast cells and basophils located in the skin, lung, gastrointestinal tract, myocardium, and vascular system [3]. Histamine release occurs as a result of interaction of vancomycin with Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2), a G-protein-coupled receptor mediating Ig-E independent mast cell degranulation [9, 10]. The fact that pretreatment with antihistamines has shown to reduce the effects of RMS further supports the histamine mediated mechanism [11]. The severity of reaction is proportional to the amount of histamine release [3]. Signs and symptoms may occur after 4–10 minutes of intravenous infusion or after its completion and even further delayed presentation have been reported [12].
Although commonly encountered with parenteral use of vancomycin, RMS has also been reported, when used in oral form [13], powder form [13] and vancomycin loaded bone cement [14]. Other antibiotics such as ciprofloxacin, amphotericin B, rifampin, and teicoplanin are also potentially linked with RMS [15]. The concomitant use of opioid analgesics, muscle relaxants, contrast dye with vancomycin seems to augment the effects of RMS [12]. Our patient did not receive any such medications and a link between past use of chemotherapy and vancomycin could not be established.
Vigilance during vancomycin infusion can identify any untoward reaction and warrant intervention. It is recommended to administer intravenous vancomycin over one to two hours duration preferably using volumetric pump with infusion rate not exceeding 10 mg/min [6] Pretreatment with antihistamines may reduce the incidence and severity of RMS [6, 11]. The infusion should be stopped right away when features of RMS is noticed and antihistamines prescribed to treat them. Corticosteroids can come to rescue in refractory cases. Occasionally, there may be the need to maintain circulation with intravenous fluids and ensure adequate oxygenation to stabilize the hemodynamics. Vancomycin desensitization is suggested in patients where the classical treatment modality is unable to stop RMS and there is the absolute need to continue vancomycin [3].
Conclusion
Vancomycin use in perioperative period is ever flourishing. This report sheds light to a rare adverse effect that can be encountered with its use. However awareness among healthcare practitioners and a well-designed protocol about the vancomycin infusion will prove worthwhile.
Abbreviations
GCSGlasgow coma scale
ICUIntensive care unit
MgMilligram
MlMilliliters
Mm of HgMillimeters of mercury
MRGPRX2Mas-related G-protein-coupled receptor X2
NSNormal saline
ROSCReturn of spontaneous circulation
RMSRed Man Syndrome
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contribution
SK was directly involved in management of the patient. He collected relevant information, designed, drafted, edited the report. SR was also involved in patient management and revised the report. Both authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient’s legal guardian(s) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33593409 | 19,721,726 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal pain'. | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | INFLIXIMAB | DrugsGivenReaction | CC BY | 33593700 | 19,612,742 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | INFLIXIMAB | DrugsGivenReaction | CC BY | 33593700 | 18,951,147 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cutaneous tuberculosis'. | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | INFLIXIMAB | DrugsGivenReaction | CC BY | 33593700 | 18,951,147 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | INFLIXIMAB | DrugsGivenReaction | CC BY | 33593700 | 19,612,742 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Immunosuppression'. | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | INFLIXIMAB | DrugsGivenReaction | CC BY | 33593700 | 19,612,742 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary tuberculosis'. | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | INFLIXIMAB | DrugsGivenReaction | CC BY | 33593700 | 19,612,742 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | INFLIXIMAB | DrugsGivenReaction | CC BY | 33593700 | 18,951,147 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tuberculosis gastrointestinal'. | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | INFLIXIMAB | DrugsGivenReaction | CC BY | 33593700 | 19,612,742 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Weight decreased'. | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | INFLIXIMAB | DrugsGivenReaction | CC BY | 33593700 | 18,951,147 | 2021 |
What was the dosage of drug 'INFLIXIMAB'? | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | 5 MG/KG | DrugDosageText | CC BY | 33593700 | 18,951,147 | 2021 |
What was the outcome of reaction 'Cutaneous tuberculosis'? | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | Recovered | ReactionOutcome | CC BY | 33593700 | 18,951,147 | 2021 |
What was the outcome of reaction 'Immunosuppression'? | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | Recovered | ReactionOutcome | CC BY | 33593700 | 19,612,742 | 2021 |
What was the outcome of reaction 'Pulmonary tuberculosis'? | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | Recovered | ReactionOutcome | CC BY | 33593700 | 19,612,742 | 2021 |
What was the outcome of reaction 'Tuberculosis gastrointestinal'? | Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease.
As the treatment of infectious and parasitic diseases improved, the prevalence of these conditions declined. However, with the expansion of the use of immunobiologicals, opportunistic infections have emerged, especially under atypical presentations. The present study reports the case of a patient treated with infliximab for Crohn's disease, who presented diarrhea, weight loss, abdominal pain, fever, and subcutaneous erythematous nodules that evolved with spontaneous fluctuation and ulceration. With the finding of alcohol-resistant bacilli and Mycobacterium tuberculosis DNA in a cutaneous fragment, through polymerase chain reaction, the diagnosis of gummatous tuberculosis was confirmed, probably secondary to hematogenous dissemination from an intestinal focus.
Immunobiologicals were introduced in the 1990s to treat inflammatory bowel diseases.1, 2, 3 Reactivation of latent infections resulting from the immunosuppression caused by these drugs may occur. Tuberculosis (TB) is more specifically associated with the use of tumor necrosis factor alpha antagonists.3
A 26-year-old female patient was diagnosed with Crohn's disease (CD) due to stomach enterorrhagia and abdominal colic. After therapeutic failure with prednisone, mesalazine, and azathioprine, infliximab 5 mg/kg was initiated. Despite the initial improvement in symptoms, she gradually worsened. After 14 months on infliximab, she maintained an active disease and weight loss, in addition to daily feverish peaks. She presented three subcutaneous erythematous nodules on the posterior region of the right thigh, of approximately 3 cm in diameter, without fluctuation or drainage. Subsequently, these lesions ulcerated, with well-defined edges and a necrotic background (Fig. 1). Histopathology showed a nonspecific inflammatory process. Intestinal endoscopic biopsy (Fig. 2) demonstrated granulomas with non-caseous central necrosis and absence of acid-alcohol-fast bacilli (AAFB; Fig. 3).Figure 1 Ulcerated nodules on the posterior region of the right thigh.
Figure 1
Figure 2 Colonoscopy showing an extensive ulcerated inflammatory process in the colon and ileum.
Figure 2
Figure 3 Non-caseating granulomas in the ileal mucosa (Hematoxylin & eosin, ×10).
Figure 3
Due to the characteristics of the granulomas, the hypothesis of infection with Yersinia pseudotuberculosis was raised. The treatment with gentamicin and ceftriaxone was ineffective, with the onset of a new erythematous cutaneous nodule on the left thigh, which revealed the presence of AAFB on histopathological examination (Fig. 4) and genetic material of Mycobacterium tuberculosis by the rapid molecular test, confirming the diagnosis of gummatous tuberculosis. Computed tomography of the chest showed nonspecific nodules, and pulmonary involvement was not ruled out. Treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was instituted for six months. The ulcerated nodules healed completely after the third month, with no recurrence after one year of follow-up.Figure 4 Presence of acid-alcohol-fast bacilli (AAFB; arrow) at histopathological examination of the skin (Ziehl-Neelsen, ×100).
Figure 4
Cutaneous TB accounts for approximately 1% of the cases of the disease.4 It can be subdivided into forms caused by direct inoculation, such as tuberculous chancre and TB verrucosa cutis, forms caused by contiguity and autoinoculation, such as scrofuloderma and periorificial TB, and forms caused by hematogenous dissemination, such as gummatous tuberculosis and acute miliary TB. Lupus vulgaris is likely to be caused through the three pathways. Tuberculids are forms in which an exacerbated immune response causes skin lesions, such as erythema induratum of Bazin, lichen scrofulosorum lichen, and papulonecrotic tuberculid.4, 5, 6
Gummatous tuberculosis is rare and affects mainly immunosuppressed and malnourished children. It is characterized by subcutaneous erythematous nodules, which evolve with intense central necrosis, fistulization, and ulceration. It results from the acute hematogenous spread of a primary outbreak during periods of bacillemia. The tuberculin test is usually negative. Histopathology shows extensive necrosis, formation of loose granulomas, and high bacillary load. Molecular techniques also contribute to the diagnosis.7 The differential diagnosis includes panniculitis, syphilitic gumma, and hidradenitis suppurativa. The morphology and location of gummatous tuberculosis helps to differentiate it from other multibacillary forms, such as periorificial. The same treatment used for lung disease is recommended. Directly monitored treatment is recommended by the National Tuberculosis Control Program of the Ministry of Health of Brazil, and must be performed at home by primary care.8, 9 After TB treatment was completed, a good response to ustekinumab for Crohn’s disease was observed.
Financial support
None declared.
Authors’ contributions
Lucas Campos Garcia: Approval of the final version of the manuscript; drafting and editing of the manuscript; collection, analysis, and interpretation of data; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature.
Everton Carlos Siviero do Vale: Approval of the final version of the manuscript; drafting and editing of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.
Maria de Lourdes Ferrari: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Lauro Damasceno de Carvalho Faria: Approval of the final version of the manuscript; intellectual participation in propaedeutic and/or therapeutic conduct of the studied cases.
Conflicts of interest
None declared.
☆ How to cite this article: Garcia LC, Vale ECS, Ferrari ML, Faria LDC. Gummatous cutaneous tuberculosis associated with the use of infliximab for Crohn's disease. An Bras Dermatol. 2021;96:228–30.
☆☆ Study conducted at Dermatology Service, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. | Recovered | ReactionOutcome | CC BY | 33593700 | 19,612,742 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal haemorrhage'. | Direct oral anticoagulants in treatment of cerebral venous thrombosis: a systematic review.
Current guidelines do not recommend direct oral anticoagulants (DOACs) to treat cerebral venous thrombosis (CVT) despite their benefits over standard therapy. We performed a systematic review to summarise the published experience of DOAC therapy in CVT.
MEDLINE, Embase and COCHRANE databases up to 18 November 2020.
All published articles of patients with CVT treated with DOAC were included. Studies without follow-up information were excluded.
Two independent reviewers screened articles and extracted data. A risk of bias analysis was performed.
Safety data included mortality, intracranial haemorrhage (ICH) or other adverse events. Efficacy data included recurrent CVT, recanalisation rates and disability by modified Rankin Scales (mRS).
33 studies met inclusion criteria. One randomised controlled trial, 5 observational cohorts and 27 case series or studies reported 279 patients treated with DOAC for CVT: 41% dabigatran, 47% rivaroxaban, 10% apixaban and 2% edoxaban, in addition to 315 patients treated with standard therapy. The observational cohorts showed a similar risk of death in DOAC and standard therapy arms (RR 2.12, 95% CI 0.29 to 15.59). New ICH was reported in 2 (0.7%) DOAC-treated patients and recurrent CVT occurred in 4 (1.5%). A favourable mRS between 0 and 2 was reported in 94% of DOAC-treated patients, more likely than standard therapy in observational cohorts (RR 1.13, 95% CI 1.02 to 1.25).
The evidence for DOAC use in CVT is limited although suggests sufficient safety and efficacy despite variability in timing and dose of treatment. This systematic review highlights that further rigorous trials are needed to validate these findings and to determine optimal treatment regimens.
Strengths and limitations of this study
We performed an all-encompassing review of patients treated with direct oral anticoagulant (DOAC) for cerebral venous thrombosis (CVT).
Given the heterogeneity of the literature, a risk of bias analysis was performed.
We compared DOAC and standard therapy in one randomised controlled trial and five observational cohorts.
Meta-analysis comparing different DOACs was not possible and is a limitation of this study.
Introduction
Cerebral venous thrombosis (CVT) requires rapid treatment to prevent neurological disability or death due to venous infarct and haemorrhage. The estimated incidence is 1 per 100 000 per year with a mean age of onset 39 years.1 Although the mortality rate has reduced to 5%–15% due to advances in detection and treatment, morbidity rates can reach as high as 20%–30%.2 A Cochrane review in 2011 showed anticoagulation to be safe in CVT and was associated with a reduction in death prompting international guidelines to recommend acute treatment of CVT with either unfractionated heparin (UFH) or low molecular weight heparin (LMWH).3–6 Longer term anticoagulation is required since recurrent venous thromboembolism (VTE) is highest within the first year of CVT.7 Thus, at least 3 months of ongoing anticoagulation in low-risk patients and indefinitely for unprovoked, high-risk patients, or those with malignancy, is recommended.6 8 The transition from acute treatment of CVT with LMWH or UFH to an oral anticoagulant, such as warfarin, is standard practice despite no randomised controlled trial (RCT) comparing warfarin with UFH or LMWH.
Direct oral anticoagulants (DOACs) were introduced to treat symptomatic VTE over the past 10 years and have advantages over warfarin: more predictable pharmacokinetics, no international normalised ratio (INR) monitoring requirement or daily dose adjustments, while demonstrating similar efficacy in treatment of acute VTE with lower rates of intracranial haemorrhage (ICH).9 Guideline recommendations, however, do not support DOAC treatment for CVT given the paucity of evidence.6 Recent larger studies on DOAC therapy for VTE in atypical locations included CVT, thus assessment of the appropriateness of these anticoagulants for the treatment of CVT is warranted.10–12
The objective of this study was to review all available evidence to assess data on safety and efficacy of DOACs in the treatment of CVT.
Methods
Search strategy and selection criteria
The protocol for this systematic review was registered (PROSPERO ID: CRD42017078398)13 and published.14 We followed Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols,15 Preferred Reporting Items for Systematic Reviews and Meta-Analyses16 and Synthesis without meta-analysis (SWiM)17 guidelines where applicable. The search strategy was iteratively developed with assistance of a research librarian (RS) and is available in the supplement (online supplemental appendix 1. We searched Ovid MEDLINE, Embase and the Cochrane Central Register of Controlled Trials for original reports of patients with a diagnosis of CVT treated with a DOAC up to 18 November 2020. We included all available peer-reviewed studies including RCTs, prospective or retrospective observational cohorts, case series and case studies. Studies without follow-up data were excluded. Two authors (GB and JG) independently reviewed titles and abstracts for inclusion.
10.1136/bmjopen-2020-040212.supp1Supplementary data
Data items
Study type and number of patients were collected. Patient data included age, sex and medical history; CVT information included location of venous thrombosis and ICH; and DOAC data included type, dosage, timing of initiation after immediate therapy and duration of treatment. Safety outcomes included mortality, occurrence of intracranial and extracranial bleeding as defined by authors and any other reported adverse events. Efficacy outcomes included recurrent CVT, recanalisation rates and disability measured by the modified Rankin Scale (mRS). The mRS is a six-point scale ranging from 0 (no symptoms) to 6 (death), with a score of 2 indicating slight disability but able to look after own affairs without assistance.18 When applicable, authors were contacted for further data.
Risk of bias analysis
We used the Cochrane Risk of Bias Tool for randomised trials;19 the Newcastle Ottawa Scale for observational cohorts;20 and Joanna Briggs Institute (JBI) Critical Appraisal Checklist for case studies and case series.21 The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework was used to assess the certainty of absolute treatment effects.22
Statistical analysis
Data were reported as counts and proportions for dichotomous data, medians and ranges for non-normally distributed continuous data, or means with SD for normally distributed continuous data. We reported risk ratios (RRs) with 95% CIs and study heterogeneity (I2) wherever possible. Case series and case report outcomes are presented as pooled descriptive statistics for each DOAC. Statistics were performed using STATA/IC V.15.1 and RevMan V.5.4.1.
Patient and public involvement
This systematic review had no individual patient involvement.
Results
Search results
Of 1843 titles, 33 studies met inclusion criteria (figure 1), representing 279 patients with CVT treated with a DOAC listed in table 1. We identified one RCT consisting of 60 patients treated with dabigatran and 60 patients treated with warfarin;23 five observational cohorts of 101 patients treated with rivaroxaban (n=80), dabigatran (n=11) and apixaban (n=10) compared with warfarin (n=301) or LMWH (n=14);24–28 six case series of patients treated with rivaroxaban (n=44), dabigatran (n=36) and apixaban (n=13);29–34 and 21 case studies of rivaroxaban (n=8), dabigatran (n=8), apixaban (n=4) and edoxaban (n=5).35–55 The clinical characteristics and outcomes of the patients are listed in table 2.
Figure 1 PRISMA flow diagram of studies included in systematic review. CVT, cerebral venous thrombosis; DOAC, direct oral anticoagulant; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Table 1 Published patients with CVT treated with DOAC
Study Year Location Anticoagulant N Study type
Bando et al43 2020 Japan Edoxaban 1 Case report
Hsu et al24 2020 USA Rivaroxaban
Apixaban 1
7 Observational cohort
Saito et al44 2020 Japan Edoxaban 1 Case report
Sugiyama et al45 2020 Japan Edoxaban 1 Case report
Chiu et al39 2020 USA Dabigatran 1 Case report
Powell et al25 2020 USA Rivaroxaban
Apixaban 12
7 Observational cohort
Bolaji et al46 2020 UK Edoxaban 1 Case report
Ferro et al23 2019 Multicentre Dabigatran 60 Randomised controlled trial
Lurkin et al26 2019 France Dabigatran
Rivaroxaban
Apixaban 2
13
1 Observational cohort
Wasay et al27 2019 Multicentre Rivaroxaban
Dabigatran 36
9 Observational cohort
Huang et al37 2019 China Dabigatran 1 Case report
Covut et al29 2019 USA Rivaroxaban
Apixaban 4
5 Case series
Hu et al38 2019 China Dabigatran 1 Case report
Rusin et al31 2019 Poland Dabigatran
Rivaroxaban
Apixaban 18
10
8 Case series
Shankar Iyer et al30 2018 India Rivaroxaban 20 Case series
Yasushi42 2017 Japan Edoxaban 1 Case report
Sui et al48 2017 China Rivaroxaban 1 Case report
Becerra et al52 2017 Argentina Dabigatran 1 Case report
Budhram et al51 2017 Canada Rivaroxaban 1 Case report
Cappellari et al32 2017 Italy Rivaroxaban 4 Case series
Hsu et al50 2017 China Rivaroxaban 1 Case report
Inche Mat et al55 2017 Malaysia Dabigatran 1 Case report
Rao et al41 2017 USA Apixaban 3 Case report
Talamo et al40 2017 USA Apixaban 1 Case report
Herweh et al28 2016 Germany Rivaroxaban
Apixaban 12
1 Observational cohort
Anticoli et al34 2016 Italy Rivaroxaban 6 Case series
Cho et al49 2016 South Korea Rivaroxaban 1 Case report
Micieli et al47 2016 Canada Rivaroxaban 1 Case report
Mendonça et al33 2015 Portugal Dabigatran 18 Case series
Mutgi et al36 2015 USA Rivaroxaban 2 Case report
Sugie et al35 2015 Japan Rivaroxaban 1 Case report
Mathew et al54 2013 India Dabigatran 1 Case report
Hon et al53 2012 Hong Kong Dabigatran 2 Case report
CVT, cerebral venous thrombosis; DOAC, direct oral anticoagulants.
Table 2 Summary of published patients with CVT treated by a DOAC
Study Anticoagulant N (%) Female Age, years Time to AC start, days AC duration, months No recanali-sation Recurrent CVT New ICH Any bleed mRS 0–2 mRS 3–5 Mortality
Randomised controlled trial
Ferro et al23 Dabigatran 60 (50) 33 (55) 45.2 (±13.8) 5–15 5.15 (±1.4) 22/55 (40) 0 (0) 0/56 (0) 12 (20) 58/59 (98.3) 1/59 (1.7) 0 (0)
Warfarin 60 (50) 33 (55) 45.2 (±13.8) 5.3 (±1.2) 17/52 (33) 0 (0) 2/53 (3.8) 12 (20) 56/58 (96.6) 2/58 (2.3) 0 (0)
Observational cohorts
Hsu et al24 Apixaban 1 (2) 5 (62) 51 (18–92) N/A N/A N/A 0 (0) 0 (0) N/A N/A 2 (25)
Rivaroxaban 7 (15)
Warfarin 38 (83) 22 (58) 43 (19–83) N/A N/A N/A 0 (0) 0 (0) N/A N/A 0 (0)
Powell et al25 Apixaban 7 (6) 8 (42) 48.1 5.3 11.03 6 (31.6) 2 (11) 0 (0) 1 (5.3) 0.78* 0 (0)
Rivaroxaban 12 (10)
LMWH Warfarin 11 (9)
89 (75) 64 (64) 43.8 11.2 13.48 31 (31) 10 (10) 3 (3) 10 (10) 1.32* 0 (0)
Lurkin et al26 Dabigatran 2 (5) 10 (62) 39.9 (16–74) N/A 6 10 (62) 0 (0) 1 (6.2) N/A 13 (81) 3 (19) 0 (0)
Apixaban 1 (2)
Rivaroxaban 13 (32)
Warfarin 25 (61) 15 (60) 47.7 (16–83) N/A 8 9/11 (82) 3/11 (27) 3 (12) N/A 6/11 (55) 5/11 (45) 0 (0)
Wasay et al27 Dabigatran 9 (8) 27 (60) 36.5 (±14.7) 7 (3–12) 8 (6–13) 1/5 (20) 0 (0) 0 (0) 2 (4) 35/39 (90) 4/39 (10) 2 (4)
Rivaroxaban 36 (32)
Warfarin 66 (59) 37 (56) 41.3 (±14.8) 5 (3–10) 3/7 (43) 0 (0) 1 (1.5) 6 (9) 44/56 (79) 12/56 (21) 4 (6)
Herweh et al28† Apixaban 1 (1) 8 (62) 41.7 (±20.5) 6 (4-9) 7 (1–84) 2 (15) 0 (0) 0 (0) 3 (23) 13 (100) 0 (0) 0 (0)
Rivaroxaban 12 (12)
LMWH 3 (3) 73 (85) 37.4 N/A 11 (13) 0 (0) 1 (1) 2 (2.3) 76 (88) 8 (9.3) 2 (2.3)
Warfarin 83 (84)
Case series
Covut et al29 Apixaban 5 (56) 4 (80) 62 (±21) 1 (1–18) 12 (6–56) 3 (60) 0 (0) 0 (0) 0 (0) 4 (80) 1 (20) 0 (0)
Rivaroxaban 4 (44) 3 (75) 57 (±22) 2 (1–30) 8 (3–14) 1 (25) 0 (0) 0 (0) 0 (0) 4 (100) 0 (0) 0 (0)
Rusin et al31 Dabigatran 18 (50) 21 (58.3) 40.3 (±9.2) 6 (IQR 5–8.8) 8.5 (IQR 6.2–12) 2 (5.6) 2 (5.6) 0 (0) 3 (8.3) 34 (94.4) 2 (5.6) 0 (0)
Apixaban 8 (22)
Rivaroxaban 10 (2)
Shankar Iyer et al30 Rivaroxaban 20 (100) 4 (20) 34.2 (±13.2) 0 (0–0) 6 0 (0) N/A 0 (0) 0 (0) 20 (100) 0 (0) 0 (0)
Cappellari et al32 Rivaroxaban 4 (100) 4 (100) 31.2 (±7.1) 4 (3–8) 4.5 (3–6) 0 (0) N/A 0 (0) N/A 4 (100) 0 (0) 0 (0)
Anticoli et al34 Rivaroxaban 6 (100) 6 (100) 36.5 (16–46) 7 (4–90) 4 (3–5) 0 (0) 0 (0) 0 (0) 0 (0) 6 (100) 0 (0) 0 (0)
Mendonça et al33‡ Dabigatran 18 (100) 15 (83.3) 41.2±13.8 13 (4–58) 7 (3–41) 3 (16.7) 0 (0) 0 (0) 0 (0) 17 (94.4) 1 (5.6) 0 (0)
Pooled case studies
Dabigatran37–39 52–55 8 (32) 5 (62) 37.9 13/7 3.7 0 (0) 0 (0) 1 (12) 1 (12) 100 0 0
Apixaban40 41 4 (16) 2 (50) 27.7 6 5.6 0 (0) 0 (0) 0 (0) 0 (0) 100 0 0
Rivaroxaban35 36 47–51 8 (32) 4 (50) 38.4 37/4 6.6 0 (0) 0 (0) 0 (0) 0 (0) 100 0 0
Edoxaban42–46 5 (20) 2 (40) 56.6 12/2 6.7 0 (0) 0 (0) 0 (0) 0 (0) 100 0 0
Data is shown as a number (%), median (range) or mean (±SD), unless otherwise stated.
*If data are not available for all patients, the denominator is shown: mean mRS at follow-up reported.
†If data are not available for all patients, the denominator is shown: patient level data were acquired from contacting authors.
‡If data are not available for all patients, the denominator is shown: data from three additional patients were included from contacting authors.
AC, anticoagulation; CVT, cerebral venous thrombosis; DOAC, direct oral anticoagulant; ICH, intracranial haemorrhage; LMWH, low molecular weight heparin; mRS, modified Rankin Scale.
Dabigatran
A total of 115 patients (41.2%) were treated with dabigatran. In a multicentre, open-label, blinded end-point RCT by Ferro et al, ‘A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis’ (RE-SPECT CVT, NCT02913326)23 patients were initially treated with LMWH or UFH for 5–15 days, followed by dabigatran 150 mg twice daily for 24 weeks. No patient died in the study. No new ICH occurred in the dabigatran group, while two occurred in the warfarin group. There were seven patients (11.7%) who discontinued dabigatran due to adverse events: one for worsening CVT-related baseline ICH, one intestinal haematoma and five non-bleeding adverse events. None of the four (6.7%) patients who discontinued warfarin did so due to adverse events. Follow-up data on 55 dabigatran-treated patients showed no radiographic CVT improvement in 40%, compared with 33% treated with warfarin (RR 1.22, 95% CI 0.74 to 2.03, p=0.44). At 24 weeks, a favourable mRS of 0–2 was reported in 58 of 59 (98.3%) in the dabigatran group and 56 of 58 (96.6%) in the warfarin group (p=0.62).
Descriptive studies of dabigatran reported an additional 44 patients. A case series by Mendonça et al33 provided patient-level data on request for 18 patients treated initially with UFH for a median 13 days followed by dabigatran for a median 6 months, 150 mg twice daily in 16 patients (89%) and 110 mg twice daily in two patients (11%). No deaths or ICH were reported, though one patient (6%) had a major intestinal bleed and one (6%) had minor intestinal bleed. At 6 months, mRS of 0 or 1 was reported in 15 patients (83%) and one (6%) had mRS of 3 (moderate disability, dependent on others but can walk). Rusin et al31 reported pooled data on 18 patients with dabigatran, 150 mg twice daily in 16 and 110 mg twice daily in 2, as well as rivaroxaban 20 mg daily in 10 and apixaban 5 mg twice daily in eight patients treated for a median of 8.5 months. During the 30-month follow-up, no death or ICH was reported, but three (8.3%) had major bleeding. Recurrent CVT occurred in two (5.6%) at 5 and 20 months after DOAC completion. Complete recanalisation occurred in 10 on dabigatran (55.6%), 6 on rivaroxaban (60.0%) and 6 on apixaban (50.0%). At 6–12 months after CVT, an excellent mRS of 0 or 1 was reported in 24 patients (66.7%), independent mRS of 2 in 10 (27.8%) and two (5.6%) had significant disability. Case studies of dabigatran reported one new ICH due to development of a dural arteriovenous fistula (DAVF) despite a reportedly complete recanalisation of their CVT37 and one myocardial infarction in the context of double thrombophilia from both plasminogen activator inhibitor-1 (PAI-1) 4G/4G homozygous genotype and protein C and S deficiency and required transition to warfarin.39 Otherwise, no patient had reported mortality, and all eight case studies reported an mRS of 0 or 1 after treatment.37–39 52–55
Rivaroxaban
A total of 132 patients (47.3%) were treated with rivaroxaban. Five observational cohorts pooled 101 DOAC-treated patients, 80 (79%) on rivaroxaban, 11 (11%) on dabigatran 150 mg twice daily and 10 (10%) on apixaban, compared with 315 on standard therapy with 301 (96%) warfarin and 14 (4%) LMWH.24–28 Patients were treated with DOAC for an average 8.1 months and with standard therapy for 9.8 months. Deaths were reported in four patients treated with a DOAC compared with six on standard therapy (RR 2.12, 95% CI 0.29 to 15.59, p=0.46, I2=49%) (figure 2). Hsu et al24 reported two deaths after DOAC therapy (25%): one in hospital from respiratory failure postaspiration in a patient treated with apixaban, and another due to metastatic lung cancer 1 year after CVT. Wasay et al27 reported two deaths in their DOAC group (4%): one prior to discharge and one prior to 6-month follow-up, and four deaths in their warfarin group (6%): three prior to discharge and one prior to 6-month follow-up. The causes of death were not reported. Herweh et al28 reported two deaths in their cohort (2%), and on request for patient-level data, none were treated with a DOAC. No significant difference between DOAC or standard therapy was reported for ICH (1% vs 2.5%, RR 0.72, 95% CI 0.18 to 2.85, p=0.64, I2=0%), recurrent CVT (5.7% vs 11.7%, RR 0.45, 95% CI 0.05 to 4.40, p=0.49, I2=54%) or incomplete recanalisation (35.8% vs 26.5%, RR 0.84, 95% CI 0.58 to 1.21, p=0.35, I2=0%) available in the supplement (online supplemental appendix 2). A favourable functional outcome of mRS 0–2 was reported in 61 of 69 (88.4%) DOAC-treated patients compared with 126 of 156 (80.7%) on standard therapy (RR 1.13, 95% CI 1.02 to 1.25, p=0.02, I2=0%) (figure 3).
10.1136/bmjopen-2020-040212.supp2Supplementary data
Figure 2 Forest plot comparing all-cause mortality between direct oral anticoagulant (DOAC) and standard therapy (warfarin, low molecular weight heparin or unfractionated heparin) for cerebral venous thrombosis.
Figure 3 Forest plot comparing favourable functional outcome of modified Rankin Scale (mRS) of 0–2 between direct oral anticoagulant (DOAC) and standard therapy (warfarin, low molecular weight heparin or unfractionated heparin) for cerebral venous thrombosis.
Descriptive studies of rivaroxaban reported an additional 52 patients. A case series by Shankar Iyer et al30 treated 20 stable patients with rivaroxaban acutely at 15 mg twice daily for 3 weeks followed by 20 mg daily. At 6-month follow-up, no patient died or discontinued rivaroxaban. There was no ICH or adverse effects reported. There was recanalisation in all patients and 19 (95%) reported mRS of 0 or 1, with mRS of 2 in only one (5%). Other case series and studies of rivaroxaban reported no mortality or ICH, and all had mRS 0 or 1 at follow-up.32 34–36 47–51 The dosing of rivaroxaban was variable: most received 20 mg daily after initial standard therapy,32 one with antiphospholipid syndrome received 15 mg daily after suffering a stroke with haemorrhagic transformation 3 months after starting warfarin for CVT,35 two received 10 mg daily in the context of Crohn’s disease49 and pegylated asparaginase for acute lymphoblastic leukaemia,48 and one was treated with 5 mg daily, in conjunction with plasma exchange (PLEX), for concurrent anti-N-methyl-D-aspartate (NMDA) receptor encephalitis.50 One patient was initially treated with rivaroxaban 15 mg twice daily and was then switched to dabigatran due to low anti-Xa levels in the context of concurrent phenytoin use for seizures secondary to CVT.52
Apixaban
Apixaban has been reported in 27 patients (9.7%).29 40 41 In the series reported by Covut et al29, five patients were treated with apixaban and four patients with rivaroxaban after a median 3 days of UFH and continued for a median of 12 months. No patient died or had new ICH during the follow-up, nor switched off their DOAC. One patient was switched onto apixaban due to gastrointestinal bleeding on warfarin and another was switched onto rivaroxaban 30 days after starting warfarin due to INR fluctuations. No recanalisation was reported in three patients (60%) on apixaban and one patient (25%) on rivaroxaban. At 6-month follow-up, mRS was 0 or 1 in eight patients (89%) and one patient had persistent mRS of 4 (unable to walk unassisted). The other case studies of apixaban indicate that all four patients had mRS of 0–1 after treatment, with no mortality or new ICH. Apixaban dosing was 5 mg twice daily for all patients, though one received 10 mg twice daily initially for 7 days in the context of T cell acute lymphoblastic leukaemia treated with pegylated asparaginase.40
Edoxaban
Edoxaban was reported in case studies of five patients (1.8%).37–41 No death, ICH, recurrent CVT or incomplete recanalisation was reported, and all patients had a good functional outcome. Two of the reported patients developed CVT in the context of COVID-19 infection and recovered without neurological sequelae.45 46
Risk of bias
The risks of bias analyses are available in the supplement (online supplemental appendix 3). In RE-SPECT CVT, patients and treating teams were aware of treatment allocation.23 No observational cohort controlled for confounders. Treatment initiation time was not reported in two observational cohorts, and follow-up duration was not standardised.24 26 The case series and case studies are moderately biased based on JBI Critical Appraisal, given lack of reporting completeness. Based on the currently available studies, the GRADE certainty is low for the absolute treatment effect.
10.1136/bmjopen-2020-040212.supp3Supplementary data
Discussion
We found that since the approval of DOAC for treatment of VTE, 279 patients treated with DOAC for CVT have been published with follow-up data. Of these patients, 42% are reported in case studies or case series, 36% in five observational cohorts and 22% in one RCT. There were 200 patients (72%) published in 2019 and 2020, suggesting that practitioner comfort for DOAC use in CVT is improving despite a lack of guideline recommendations.6 A recent survey of Canadian neurologists and haematologists suggests interest in the utilisation of DOAC for treatment of CVT, and the increasing reports support this trend.56
Outcomes of DOAC compared with standard therapy
Currently, warfarin is supported by guidelines despite no RCT evidence of superiority or non-inferiority to LMWH or UFH. The benefits of the DOAC over warfarin include reduced dose adjustments due to drug and food interactions, no need for INR monitoring to ensure therapeutic range and, in the case of dabigatran, the availability of a reversal agent. Furthermore, even when closely monitored in a clinical trial setting, patients on warfarin for CVT were in the therapeutic INR range only 66% of the time,23 suggesting better anticoagulation may be achieved with DOAC. Overall safety of DOAC was reassuring, with recurrent CVT, new ICH and death only reported in observational cohorts at rates similar to standard therapy and within the expected range of treated CVT.2 Furthermore, of the DOAC-treated patients who died, two of four deaths occurred after discharge, including one related to underlying metastatic cancer that would not suggest DOAC-related mortality.24 Efficacy was also promising with 93% of DOAC-treated patients attaining a favourable outcome of mRS from 0 to 2 compared with 85% of those on standard therapy. Compared with standard therapy in the observational cohorts, this value was higher for DOAC-treated patients. However, utilisation of DOAC in less severe CVT cannot be ruled out as a confounding factor since the observational cohorts did not have comparable standard treatment groups.
A meta-analysis published by Lee et al57 showed similar results to our review with no difference between DOAC or warfarin for recanalisation rates or major bleeding; however, their review analysed an ‘excellent’ mRS outcome of 0–1 and found no difference, while our study analysed a ‘favourable’ mRS of 0–2 and found a difference in the observational cohorts. The dichotomy of a favourable mRS has been debated, with mRS greater than two shown to be related to 1-year mortality, as well as being an independence cut-off for entry to certain endovascular trials.58–60 The apparent discrepancy may also relate to two of their analysed observational cohort studies (Geisbüsch et al61 and Herweh et al28) potentially including patients from the same institution during overlapping time periods (January 2012–December 2013 and January 1998–September 2014, respectively). To clarify, we were able to contact the authors from these studies and obtain patient-level data, which led to the exclusion of Geisbüsch et al61 due to duplicate patient data. Furthermore, we have updated the search to include an additional two cohorts published in 2020.
An ongoing RCT out of University of British Columbia, the ‘Study of Rivaroxaban for CeREbral Venous Thrombosis’ (SECRET, NCT03178864), is currently recruiting an estimated 50 participants comparing rivaroxaban with standard anticoagulation of LMWH, UFH or warfarin, expected to be completed December 2021.62 Another RCT, ‘Rivaroxaban vs Warfarin in CVT Treatment’ (RWCVT, NCT04569279) out of Damascus University has completed enrollment of 71 patients though not yet published results.63 Results of these studies will be useful for future guideline recommendations for DOAC use in CVT compared with standard therapy.6
Comparison between different DOAC
Our search yielded no randomised trials comparing different DOAC against each other, thus no formal meta-analysis comparing different DOAC was possible. Dabigatran was compared against warfarin in the only published RCT specifically looking at CVT to date; however, the most commonly reported DOAC was rivaroxaban, possibly suggesting physician comfort with this medication. Results from RWCVT and SECRET will help validate safety and efficacy of rivaroxaban and allow more definitive comparison with dabigatran from RE-SPECT CVT.62
The timing of DOAC initiation after acute treatment with LMWH or UFH ranged from 5 to 15 days for the RCT and from 3 to 12 days for the observational cohorts. The descriptive studies had more variability in DOAC initiation, ranging from acutely after CVT diagnosis, to as far as 3 months, making comparisons challenging. The dosage of DOAC was also inconsistent, with dabigatran dose ranging from 75 mg to 150 mg twice daily in the cohort by Wasay et al27 and rivaroxaban dosing between 5 mg daily and 20 mg daily depending on the study. Both ongoing RCTs use rivaroxaban after initial acute therapy with LMWH or UFH, for SECRET 20 mg daily within 14 days of CVT diagnosis, and for RWCVT 20 mg or 15 mg, depending on creatinine clearance, after a non-specified duration of acute therapy. These and future trials should help standardise how long initial therapy with LMWH or UFH is needed, if at all, prior to using DOAC, as well as if initial dosage adjustments are needed.
There were rare adverse events with each DOAC therapy. For dabigatran, no deaths were reported, and of the patients who experienced bleeding, none were given the reversal agent. However, in RE-SPECT CVT, dabigatran was stopped in two patients due to intestinal haematoma and worsening of the haemorrhagic component of their baseline intracranial lesion.23 Bleeding events on rivaroxaban were only reported in the series by Rusin et al31 in three patients (8.3%), two on 20 mg daily rivaroxaban and one on 110 mg twice daily dabigatran, who had heavy menstrual bleedings in two and upper gastrointestinal bleeding in one. Other rare adverse events include the in-hospital death of a patient treated with apixaban who had an aspiration event and respiratory failure,24 myocardial infarction while on dabigatran39 and DAVF formation 3 months after CVT despite complete recanalisation with dabigatran.37 A post hoc analysis of the RE-SPECT CVT showed no DAVF formation at 6 months.64 Two case studies of edoxaban treated patients with CVT in the context of COVID-19.45 46 Thrombotic complications of COVID-19 has been reported, but the safety and efficacy of DOAC in COVID-19 related thrombosis specifically has yet to be confirmed.65 66
The efficacy of each DOAC was good for treatment of CVT. Recurrent CVT was only reported in four patients overall (1.5%), two patients from the cohort Powell et al25 (11%) and two in the case series Rusin et al31 (5.6%) after discontinuation of DOAC. An international long-term cohort found the rate of recurrent CVT is as high as 4.4% at median 40 months; therefore, long-term follow-up of DOAC-treated CVT is needed to determine the ideal treatment duration.67 Recanalisation rates varied between DOAC treatment at similar rates reported in randomised trials of LMWH and UFH to treat CVT3–5 without clear reduction of a favourable functional outcome, as previously demonstrated.28 However, the prognostic value of recanalisation has been investigated by a meta-analysis of standard therapy, which showed recanalisation occurred in up to 85% of patients and was associated with mRS 0 or 1 (OR 3.3, 95% CI 1.7 to 6.3, p=0.001).68 Further high-quality studies will be required to determine if recanalisation rates differ between DOACs, as well as if they are related to functional outcome.
Limitations
The results of this systematic review should be interpreted with caution. The majority of patients were reported in retrospective observational cohorts or case studies prone to selection bias, confounding and lack of standardisation in timing of therapy initiation and follow-up duration. Therefore, pooling and inferential statistical analysis was not prudent due to the clinical and methodological heterogeneity and conclusions as to how DOAC therapies perform against each other could not be made. The risk of bias analysis revealed that RE-SPECT CVT has the lowest bias risk given utilisation of a Prospective Randomized Open, Blinded End-point (PROBE) design, and although the retrospective studies inherently have increased bias, most studies were appropriately informative. Finally, follow-up data and treatment duration were limited to a median 6 months; longer term registries for safety will be needed to estimate rates of recurrent CVT in patients treated with a DOAC.
Unanswered questions and future research
Our systematic review suggests physicians are increasingly using DOAC for the treatment of CVT; however, several remaining questions require further study. The ideal time to start a DOAC after diagnosis of CVT is not known. Certain studies first use LMWH or UFH treatment, while others used a DOAC acutely. The safety of DOAC use in children is not known. The recently published RCT, ‘Oral Rivaroxaban in Children With Venous Thrombosis’ (EINSTEIN-JR, NCT02234843), investigated paediatric cases of any acute VTE and randomised to weight-based rivaroxaban or standard anticoagulation showed potentially improved thrombotic burden (OR 1.70, p=0.012) and similar safety as adult studies.69 Specific outcomes were not reported based on VTE location; however, 74 of 335 (22%) patients treated with rivaroxaban had CVT, and no clear safety concern was identified. Finally, the ideal DOAC to use for CVT also requires further study. Results from RWCVT and SECRET will help validate safety and efficacy of rivaroxaban and allow more definitive comparison with dabigatran from RE-SPECT CVT.62 Although dabigatran has the advantage of having a reversal agent, idaricizumab, its use in CVT has not been published at the current time, so any unique risks in this population is unknown.70 Extrapolating conclusions for apixaban or edoxaban from studies of different DOAC may give an inaccurate risk–efficacy profile, and thus high-quality RCT of these treatments are also needed.
Given that CVT is a rare disease, enrolment in these large randomised studies is slow, so review of observational cohorts and smaller studies provide needed information. Physicians recognise the benefits of DOACs and are increasingly using these medications for treatment of CVT despite the lack of guideline recommendations. Based on this review, no clear safety concerns are identified for any particular DOAC, and the available data on efficacy is promising. The ideal timing for initiation of DOAC after diagnosis of CVT, and the ideal DOAC to use for CVT, are remaining questions. The results of future RCTs may inform guidelines if no adverse safety signal and a similar efficacy to standard therapy is seen.
Supplementary Material
Reviewer comments
Author's manuscript
Contributors: GB, JG, DD and RS developed the search strategy; GB, JG and DD reviewed articles for inclusion; GB, DAF and DD performed data analysis; VY assessed articles for risk of bias; GB wrote the manuscript; GLG, JC, MM, MV-B and SN contributed expert opinion and revised research question and discussion, and all authors revised the manuscript for intellectual content and approved the final manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: GB: none. JG: none. VY: none. RS: none. DAF: none. GLG holds an Early Researcher Award from the Ontario Ministry of Research and Innovation (MRI); an Ontario Mid-Career Investigator Award from the Heart and Stroke Foundation of Canada; and a University of Ottawa, Faculty of Medicine Tier 1 Clinical Research Chair in Diagnosis of Venous Thromboembolism. He has indirectly received research funding from Portola, Boehringer-Ingelheim, Pfizer, Bristol-Myers Squibb, LEO Pharma, Daiichi Sankyo, Bayer. He has received speaker honoraria from Bayer, Pfizer, LEO Pharma, Sanofi bioMérieux. JC: has received research funding from the following non-profit organisations: Dutch Heart Foundation, Dutch Brain Foundation and Amsterdam Neuroscience. He has also received research support from Bayer, Boehringer and Portola. All fees were paid to his institute and used to fund medical research. MM: none. MV-B received speaker fees from Boehringer Ingelheim, Portugal, is part of an advisory board of Daiichi Sankyo, Portugal, and received a travel grant from Boehringer Ingelheim, Portugal. SN: received consulting fees from Brainomix and Böhringer Ingelheim and Honoria for lectures from Bayer, BMS Pfizer and Medtronic. DD received a Heart & Stroke Foundation of Canada Clinician Scientist Award, and has received honoraria from Bayer, BMS and Apopharma.
Patient consent for publication: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: Data are available in a public, open access repository. Extra data can be accessed via the Dryad data repository at http://datadryad.org/ with the doi:10.5061/dryad.37pvmcvgn.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | APIXABAN, DABIGATRAN ETEXILATE MESYLATE, RIVAROXABAN | DrugsGivenReaction | CC BY-NC | 33593766 | 19,060,789 | 2021-02-16 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Conjunctival follicles'. | Primary treatment of ocular surface squamous neoplasia with topical interferon alpha-2b: Comparative analysis of outcomes based on original tumor configuration.
The aim of this study was to evaluate tumor control of OSSN with topical IFNα2b alone based on tumor configuration (flat versus (vs.) dome-shaped).
Retrospective, nonrandomized, interventional cohort study on 64 consecutive tumors in 63 patients with OSSN treated with topical IFNα2b. Topical IFNα2b (1 million international units/cc) was compounded and provided by the Thomas Jefferson University Hospital Pharmacy to be refrigerated and applied 4 times daily until biomicroscopic evidence of tumor resolution was observed.
The tumor configuration was flat (n = 15, 23%) or dome-shaped (n = 49, 77%). A comparison (flat vs. dome-shaped) revealed dome-shaped with older mean patient age at presentation (62 vs. 70 years, P = 0.04), greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (7% vs. 82%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean thickness (1.9 vs. 4.3, P = 0.002), and longer mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002). There was no difference in mean follow-up time (22.2 vs 23.1 months) or time to complete response (5.0 vs. 6.1 months). There was no difference in achievement of complete tumor control with IFNα2b alone (93% vs. 96%). There were no cases with metastasis or death.
Topical IFNα2b alone shows excellent overall tumor control of 95% with no difference in efficacy based on tumor configuration.
Ocular surface squamous neoplasia (OSSN) is an umbrella term referring to the spectrum of squamous epithelial malignancy that can occur on the ocular surface, from in situ mild dysplasia to invasive epithelial malignant tumors. Based on the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study of 566,401 individuals aged 50-71 years, the incidence of OSSN was 8.4 per million persons, and found to be greater incidence in males (10.3 per million) and age >60 years (10.0 per million).[1] The management of this malignancy involves surgical and non-surgical alternatives, using topical or injection chemotherapy or immunotherapy. Several publications have explored the role of topical interferon alpha 2-B (IFNα2b) for tumor management.[123] A matched comparative analysis (IFNα2b (topical and injections) versus (vs.) surgery) for OSSN therapy revealed no difference in the recurrence rate (3% vs. 5%)[4] and non-significant equivalent cost for the full course of the two alternatives ($2831 vs $3528 US dollars (Medicare allowable charges)).[5] Thus, topical and injection IFNα2b for OSSN remains an important therapeutic alternative to surgery for affected patients.
Herein, we specifically focus on the role of topical IFNα2b monotherapy in the management of OSSN. In this analysis, we explore tumor control with topical IFNα2b based on tumor configuration (flat versus (vs.) dome-shaped). Many clinicians using topical therapies apply the medications based on classic tumor features and without the need for tumor biopsy, to spare the patient surgical intervention. Thus, tumor grouping by the American Joint Committee on Cancer (AJCC) Classification is not possible, as histopathology evaluation of tumor depth (in situ vs. deeper) is not available. However, one might speculate that tumor configuration as flat could serve as a surrogate for Tis and configuration as dome-shaped could represent T1, T2, T3, or T4 based on tumor basal dimension and adjacent tissue involvement as proposed by the AJCC.[6] Herein, we explore outcomes of topical IFNα2b based on practical tumor configuration, whether the tumor is thin (flat) or thick (dome-shaped).
Methods
The medical records of all patients with clinically-evident OSSN diagnosed and managed on the Ocular Oncology Service at Wills Eye Hospital, Philadelphia USA, between October 4, 2005, and January 28, 2019 were retrospectively reviewed. Patients were included if primary treatment for OSSN consisted only of topical IFNα2b monotherapy. Patients who received treatment prior to referral, or those who received subconjunctival injection of IFNα2b or were treated with prophylactic IFNα2b were excluded. The treatment protocol included use of IFNα2b (Intron-A, Schering-Plough, London UK) in a topical formulation of 1 million international units (IU)/mL compounded by Thomas Jefferson University Hospital Pharmacy, Philadelphia USA, and stored in refrigeration, avoiding disturbance or shaking of the bottle. The eye drops were administered 4 times daily until 1 month beyond clinical evidence of complete tumor resolution or until the time a secondary treatment was deemed necessary due to poor response. The response to treatment was monitored every 3 to 6 months and the duration of treatment was modified on the basis of tumor response. This study was approved by the Institutional Review Board of Wills Eye Hospital, Philadelphia USA and adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all patients.
All patients were examined by a trained ocular oncologist (CLS, SEL) with slit-lamp biomicroscopy, documentation on detailed, large conjunctival drawings, and with photographic documentation. The demographic data included age, race, sex, and Fitzpatrick skin type. Past medical history included risk factors of smoking status, autoimmune condition, chronic use (>6 months) of topical or systemic corticosteroids or other immunosuppressive medications, organ transplant, corneal graft, human papillomavirus (HPV) infection, human immunodeficiency virus infection, and cutaneous or mucous membrane squamous cell carcinoma. Clinical findings at presentation included best-corrected visual acuity), tumor laterality, tumor multiplicity, tissues involved (bulbar conjunctiva, forniceal conjunctiva, tarsal conjunctiva, plica semilunaris, caruncle, cornea, eyelid, and orbit), quadrant or location involved (superior, temporal, inferior, nasal, diffuse), largest tumor basal diameter, number of clock hours involved, tumor configuraton (flat, dome-shaped), lesion color, feeder and intrinsic vessels, leukoplakia, and internal pigment. The tumor configuration was considered flat if there was a flat surface of ≤1 mm thickness, whereas the tumors were considered dome-shaped if the mass gradually increased in thickness from the margin to a central apex and were >1 mm thickness centrally.
The number of months of topical IFNα2b therapy were recorded. At each follow-up examination, features were recorded regarding best-corrected visual acuity, tumor basal diameter, tissue involvement, and interferon-induced toxicity. Treatment outcomes included tumor control (complete, partial, or no response), recurrence, treatment for recurrence, metastasis, and death. Complete response was defined as complete tumor regression with total disappearance of tumor. Partial response was defined as tumor regression of less than 100%. No response was defined as no visible change following therapy. Recurrence was defined as reappearance of tumor at the primary tumor location after complete resolution following topical IFNα2b. Additional treatment required for tumor control after primary topical IFNα2b was noted. Spread to regional lymph nodes was assessed by history and palpation of preauricular, submental, submandibular, and cervical lymph nodes at each visit. Distant metastasis and death per the general medical physician were recorded.
Demographics, clinical features, and outcomes were compared by tumor configuration (flat vs. dome-shaped) using Fisher's exact test, Chi-squared test, and Mann Whitney U test. A P value <0.05 was considered significant.
Results
Of the 236 consecutive patients with clinically evident OSSN evaluated and managed on the Ocular Oncology Service, Wills Eye Hospital, during this time period, there were 64 tumors in 63 eyes of 63 patients that met inclusion criteria for this study. Tumors were classified according to surface configuration (flat (thin) (n = 15, 23%) vs. dome-shaped (thick) (n = 49, 77%)).
The patient demographic features are listed in Table 1. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with older mean patient age (62 vs. 70 years, P = 0.04) and greater frequency of smoking (13% vs. 42%, P = 0.04). There was no difference regarding patient race, sex, or Fitzpatrick Skin Type, autoimmune disease, immunosuppression, medical history of squamous neoplasia elsewhere, and tumor laterality and multiplicity.
Table 1 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases of 63 Patients. Demographic features
Demographic Features Flat [Tis] (n=15 patients) [n (%)] Dome-shaped [T3] (n=48 patients) [n (%)] P Total (n=63 patients) [n (%)]
Age (years)
Mean (median, range) 62 (61, 45-85) 70 (68, 30-97) 0.04 68 (64, 30-97)
Race
Caucasian 14 (93) 45 (94) 0.67 59 (94)
African American 1 (7) 1 (2) 2 (3)
Hispanic 0 (0) 1 (2) 1 (2)
Asian 0 (0) 1 (2) 1 (2)
Sex
Male 8 (53) 27 (56) 0.84 35 (56)
Female 7 (47) 21 (44) 28 (44)
Fitzpatrick Skin Type
I 4 (27) 17 (35) 0.73 21 (33)
II 9 (60) 23 (48) 32 (51)
III 1 (7) 5 (10) 6 (10)
IV 0 (0) 2 (4) 2 (3)
V 0 (0) 0 (0) 0 (0)
VI 1 (7) 1 (2) 2 (3)
Smoking History
Yes 2 (13) 20 (42) 0.04 22 (34)
No 13 (87) 28 (58) 42 (66)
Medical History - Autoimmune
Celiac 0 (0) 1 (2) 0.77 1 (2)
Ocular cicatricial pemphigoid 0 (0) 1 (2) 0.77 1 (2)
Psoriatic arthritis 1 (7) 0 (0) 0.23 1 (2)
Rheumatoid arthritis* 0 (0) 1 (2) 0.77 1 (2)
Sjögren’s syndrome* 0 (0) 1 (2) 0.77 1 (2)
Thyroiditis 0 (0) 1 (2) 0.77 1 (2)
Medical History - Immunosuppression
Chronic systemic corticosteroids 1 (7) 2 (4) 0.56 3 (5)
Chronic systemic immunosuppressants 1 (7) 2 (4) 0.56 3 (5)
Chronic topical corticosteroids 0 (0) 1 (2) 0.99 1 (2)
Organ transplant 0 (0) 1 (2) 0.99 1 (2)
Corneal graft 0 (0) 2 (4) 0.99 2 (3)
HPV history 1 (7) 1 (2) 0.42 2 (3)
Medical History - SCC History
Skin SCC 2 (13) 6 (13) 0.93 8 (13)
Mucosal SCC** 0 (0) 2 (4) 0.99 2 (3)
Laterality
Right 4 (27) 25 (52) 0.40 29 (46)
Left 11 (73) 23 (48) 34 (54)
Multiplicity of tumors
Single 15 (100) 47 (98) 0.99 62 (98)
Multiple 0 (0) 1 (2) 1 (2)
HPV=Human papilloma virus, SCC=squamous cell carcinoma. Bold values indicate significant P. * There was one patient diagnosed with both rheumatoid arthritis and Sjögren’s syndrome. **There was one case of oropharyngeal SCC and one case of rectal SCC
The tumor features are listed in Table 2. At presentation, there was no evidence of lymph node or distant metastatic disease. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with greater corneal involvement (7%% vs. 82%, P < 0.001), greater mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and greater mean clock hour involvement (1.9 vs. 4.1, P = 0.002). There was no difference in tumor quadrant, growth pattern, color, vascularity, or additional features.
Table 2 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Tumor characteristics
Tumor Characteristics Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
Tissue involved
Bulbar 13 (87) 41 (84) 0.78 54 (84)
Fornix 0 (0) 9 (18) 0.07 9 (14)
Tarsus 2 (13) 6 (12) 0.91 8 (13)
Plica semilunaris 0 (0) 1 (2) 0.99 1 (2)
Caruncle 0 (0) 2 (4) 0.99 2 (3)
Cornea 1 (7%) 40 (82) <0.001 41 (64)
Eyelid 0 (0) 2 (4) 0.99 2 (3)
Orbit 0 (0) 0 (0) NA 0 (0)
Quadrant involved
Superior 1 (7) 4 (8) 0.97 5 (8)
Temporal 3 (20) 10 (20) 13 (20)
Inferior 2 (13) 9 (18) 11 (17)
Nasal 9 (60) 25 (51) 34 (53)
Diffuse 0 (0) 1 (2) 1 (2)
Tumor Size
Largest basal diameter (mm) Mean (median, range) 5.5 (5.0, 1.0-12.0) 12.4 (10.0, 1.5-60.0) 0.001 10.8 (8.2, 1.0-60.0)
Number of clock hours involved Mean (median, range) 1.9 (2.0, 1.0-5.0) 4.1 (3.0, 1.0-12.0) 0.002 3.6 (3.0, 1.0-12.0)
Tumor Color
Pink 2 (13) 6 (12) 0.99 8 (12)
Yellow 10 (67) 34 (69) 44 (69)
White 3 (20) 9 (18) 12 (19)
Tumor Vascularity
Intrinsic vessels 8 (53) 28 (57) 0.80 36 (56)
Feeder vessels 6 (40) 18 (37) 0.82 24 (37)
Additional features
Leukoplakia 5 (33) 8 (16) 0.15 13 (20)
Internal cysts 1 (7) 0 (0) 0.23 1 (2)
Internal pigment 0 (0) 0 (0) NA 0 (0)
Bold values indicate significant P
Topical IFNα2b at a dose of 1 million IU/mL administered 4 times daily was used as primary monotherapy for all patients. The tumor response is listed in Table 3. There was no difference in percentage of patients lost to follow-up (7% vs. 2%, P = 0.42) or mean follow-up time (22.2 vs. 23.1 months, P = 0.87). A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with longer mean duration of IFNα2b monotherapy for tumor control (3.7 vs. 6.3 months, P = 0.002). There was no difference in complete tumor response (93% vs. 96%, (P = 0.65), partial response (7% vs. 2%), or no response (0% vs. 2%) (P = 0.54) [Fig. 1]. The single patient with no response had prior corneal graft and received topical IFNα2b with no improvement, and later required subconjunctival IFNα2b injection. There was no difference regarding mean time to complete response (5.0 vs. 6.1 months, P = 0.25). Following initial response, there was no difference in tumor recurrence (7% vs. 2%, P = 0.41). Regarding local treatment side effects, flat tumors had more frequent follicular reaction (20% vs. 2%, P = 0.04). There was no difference in ocular surface irritation or corneal epithelial defect. There were no patients who developed metastatic disease or death.
Table 3 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Outcomes
Outcomes Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
No follow-up 1 (7) 1 (2) 0.42 2 (3)
Tumor response n=14 n=48 n=62
Complete 13 (93) 46 (96) 0.54 59 (95)
Partial 1 (7)* 1 (2)** 2 (3)
No response 0 (0) 1 (2)*** 1 (2)
n=14 n=47 n=61
Recurrence after initial response 1 (7) 1 (2) 0.41 2 (3)
Additional treatment needed for complete response 1 (7) 6 (13) 0.68 7 (11)
Topical mitomycin C 0 (0) 1 (2) 0.99 1 (2)
Surgical excision 1 (7) 5 (9) 0.99 6 (10)
Local treatment side effects
Follicular reaction 3 (20) 1 (2) 0.04 4 (6)
Irritation 0 (0) 1 (2) 0.99 1 (2)
Corneal epithelial defect 0 (0) 1 (2) 0.99 2 (3)
Systemic outcomes
Metastasis 0 (0) 0 (0) NA 0 (0)
Death 0 (0) 0 (0) NA 0 (0)
Total duration of interferon alpha-2b therapy (months)
Mean (median, range) 3.7 (3.0, 0.5-7.0) 6.3 (6.0, 1.0-13.0) 0.002 5.7 (5.0, 0.5-13.0)
Time to complete response (months)
Mean (median, range) 5.0 (3.8, 1.0-11.5) 6.1 (5.4, 1.3-17.8) 0.25 5.8 (5.0, 1.0-17.8)
Follow-up time (months) n=14 n=48 n=62
Mean (median, range) 22.2 (14.3, 2.9-63.1) 23.1 (13.9, 1.3-114.6) 0.87 23.0 (14.4, 1.3-114.6)
Bold values indicate significant P. * Patient lost to follow-up after 7 months of therapy due to liver transplant. ** Patient stopped interferon alpha-2b after 1 month due to ocular surface discomfort and was lost to follow-up. *** Patient elected not to continue treatment after secondary treatment was advised
Figure 1 Treatment of ocular surface squamous neoplasia (OSSN) using topical interferon alpha-2b (IFNa2b) monotherapy. Flat vascular OSSN in a 76-year-old female (a) before and (b) after 4 months of IFNa2b monotherapy. Dome-shaped OSSN in a 57-year-old female (c) before and (d) after 8 months of IFNa2b monotherapy
Discussion
A recent report of 5002 conjunctival tumors from an ocular oncology center revealed that premalignant/malignant squamous neoplasia (OSSN) represented 729 (15%) of all cases, mostly with diagnoses of conjunctival intraepithelial neoplasia (CIN) (n = 275 tumors) or squamous cell carcinoma (SCC) (n = 440 tumors).[7] In that analysis, CIN or SCC was most often noted at the corneoscleral limbus (575/715, 80%), located nasally (269/715, 38%) or temporally (285/715, 40%), and appearing as a lump/swelling to the patient (434/715, 61%).
In 2012, Shah et al. reported the results of topical v for OSSN in 23 cases based on the 7th edition AJCC classification and noted that complete control was achieved in 83% of cases, specifically 67% of those labeled as Tis and 85% of the T3 group.[8] In that analysis there were no patients with T1, T2, or T4, as found in our current study. Further investigation of topical or injection IFNα2b for OSSN revealed applications for immunoreduction of giant OSSN, and immunoprevention in immunosuppressed patients, especially those with human immunodeficiency virus (HIV) or organ transplant who are at risk to have numerous and multifocal OSSN.[910] Galor et al. compared the topical dose of 1 million IU/ml to 3 million IU/mL IFNα2b and found no difference in tumor response, treatment duration, recurrence, or adverse effects.[11]
Since the above publications, the AJCC has been updated to the 8th edition. However, classification requires tumor biopsy and histopathologic analysis, but in this current era of topical therapies, clinicians often avoid biopsy when starting topical therapies if the diagnosis is clinical evident. Thus, AJCC classification is not possible for clinicians using purely topical therapies. In this report, we accommodate AJCC 8th edition classification by inferring that flat tumor configuration with no corneal component might serve as a surrogate for Tis and dome-shaped as T1, T2, T3, or T4.
In this analysis, we were able to provide a comparative analysis of tumor control with topical IFNα2b monotherapy without the need for biopsy. We found important differences in clinical features in that dome-shaped tumors occurred in older mean patient age (62 vs. 70 years, P = 0.04), with greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (0% vs. 84%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean clock hour extent (1.9 vs. 4.3, P = 0.002). To achieve control with topical IFNα2b, dome-shaped tumors tumors required greater mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002) for equivalent complete tumor control (93% vs. 96%, P = 0.65).
There are limitations to this study that should be considered. The data was a retrospective collection with inherent biases and drawbacks. Additionally, the cohort size was relatively small at 64 cases, resulting in limited statistical power, but due to the rarity of this malignancy and strict inclusion criteria of primary treatment with topical IFNα2b monotherapy only, our data represents pure data with few conflicting events. We recognize that precise AJCC classification could not be performed without histopathologic anaylsis, and microscopic invasion of the basement membrane in the case of flat tumor could have been missed. Nevertheless, with excellent tumor control for both flat and dome-shaped tumor, biopsy would not likely have changed our main study conclusion. Perhaps further studies could evaluate outcomes based on clinical imaging such as anterior segment optical coherence tomography or ultrasound biomicroscopy. Lastly, further follow-up with larger cohort in the future could potentially verify our observations.
Most previous studies on this topic have included pretreatment biopsy for diagnostic and staging confirmation, but that interferes with the ability to promptly employ some topical therapies and adds a confounding factor of the amount of tumor surgically excised versus the remnant of tumor left for treatment with topical therapy. Hence, we chose to avoid biopsy as this is consistent with how most clinicians currently approach clinically-evident OSSN, especially when starting topical therapy. Thus our results reflect the impact of topical IFNα2b monotherapy for the entire OSSN without the need for biopsy.
Conclusion
In conclusion, based on tumor configuration of OSSN, overall tumor control is 95% and does not differ when comparing flat to dome-shaped tumors. In addition, dome-shaped tumors required longer duration of therapy and demonstrated no greater recurrence upon discontinuation of the medication. We conclude that topical IFNα2b monotherapy is highly effective for the treatment of conjunctival OSSN, whether or not the tumor is flat or dome-shaped.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | INTERFERON ALFA-2B | DrugsGivenReaction | CC BY-NC-SA | 33595473 | 19,031,058 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Corneal epithelium defect'. | Primary treatment of ocular surface squamous neoplasia with topical interferon alpha-2b: Comparative analysis of outcomes based on original tumor configuration.
The aim of this study was to evaluate tumor control of OSSN with topical IFNα2b alone based on tumor configuration (flat versus (vs.) dome-shaped).
Retrospective, nonrandomized, interventional cohort study on 64 consecutive tumors in 63 patients with OSSN treated with topical IFNα2b. Topical IFNα2b (1 million international units/cc) was compounded and provided by the Thomas Jefferson University Hospital Pharmacy to be refrigerated and applied 4 times daily until biomicroscopic evidence of tumor resolution was observed.
The tumor configuration was flat (n = 15, 23%) or dome-shaped (n = 49, 77%). A comparison (flat vs. dome-shaped) revealed dome-shaped with older mean patient age at presentation (62 vs. 70 years, P = 0.04), greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (7% vs. 82%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean thickness (1.9 vs. 4.3, P = 0.002), and longer mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002). There was no difference in mean follow-up time (22.2 vs 23.1 months) or time to complete response (5.0 vs. 6.1 months). There was no difference in achievement of complete tumor control with IFNα2b alone (93% vs. 96%). There were no cases with metastasis or death.
Topical IFNα2b alone shows excellent overall tumor control of 95% with no difference in efficacy based on tumor configuration.
Ocular surface squamous neoplasia (OSSN) is an umbrella term referring to the spectrum of squamous epithelial malignancy that can occur on the ocular surface, from in situ mild dysplasia to invasive epithelial malignant tumors. Based on the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study of 566,401 individuals aged 50-71 years, the incidence of OSSN was 8.4 per million persons, and found to be greater incidence in males (10.3 per million) and age >60 years (10.0 per million).[1] The management of this malignancy involves surgical and non-surgical alternatives, using topical or injection chemotherapy or immunotherapy. Several publications have explored the role of topical interferon alpha 2-B (IFNα2b) for tumor management.[123] A matched comparative analysis (IFNα2b (topical and injections) versus (vs.) surgery) for OSSN therapy revealed no difference in the recurrence rate (3% vs. 5%)[4] and non-significant equivalent cost for the full course of the two alternatives ($2831 vs $3528 US dollars (Medicare allowable charges)).[5] Thus, topical and injection IFNα2b for OSSN remains an important therapeutic alternative to surgery for affected patients.
Herein, we specifically focus on the role of topical IFNα2b monotherapy in the management of OSSN. In this analysis, we explore tumor control with topical IFNα2b based on tumor configuration (flat versus (vs.) dome-shaped). Many clinicians using topical therapies apply the medications based on classic tumor features and without the need for tumor biopsy, to spare the patient surgical intervention. Thus, tumor grouping by the American Joint Committee on Cancer (AJCC) Classification is not possible, as histopathology evaluation of tumor depth (in situ vs. deeper) is not available. However, one might speculate that tumor configuration as flat could serve as a surrogate for Tis and configuration as dome-shaped could represent T1, T2, T3, or T4 based on tumor basal dimension and adjacent tissue involvement as proposed by the AJCC.[6] Herein, we explore outcomes of topical IFNα2b based on practical tumor configuration, whether the tumor is thin (flat) or thick (dome-shaped).
Methods
The medical records of all patients with clinically-evident OSSN diagnosed and managed on the Ocular Oncology Service at Wills Eye Hospital, Philadelphia USA, between October 4, 2005, and January 28, 2019 were retrospectively reviewed. Patients were included if primary treatment for OSSN consisted only of topical IFNα2b monotherapy. Patients who received treatment prior to referral, or those who received subconjunctival injection of IFNα2b or were treated with prophylactic IFNα2b were excluded. The treatment protocol included use of IFNα2b (Intron-A, Schering-Plough, London UK) in a topical formulation of 1 million international units (IU)/mL compounded by Thomas Jefferson University Hospital Pharmacy, Philadelphia USA, and stored in refrigeration, avoiding disturbance or shaking of the bottle. The eye drops were administered 4 times daily until 1 month beyond clinical evidence of complete tumor resolution or until the time a secondary treatment was deemed necessary due to poor response. The response to treatment was monitored every 3 to 6 months and the duration of treatment was modified on the basis of tumor response. This study was approved by the Institutional Review Board of Wills Eye Hospital, Philadelphia USA and adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all patients.
All patients were examined by a trained ocular oncologist (CLS, SEL) with slit-lamp biomicroscopy, documentation on detailed, large conjunctival drawings, and with photographic documentation. The demographic data included age, race, sex, and Fitzpatrick skin type. Past medical history included risk factors of smoking status, autoimmune condition, chronic use (>6 months) of topical or systemic corticosteroids or other immunosuppressive medications, organ transplant, corneal graft, human papillomavirus (HPV) infection, human immunodeficiency virus infection, and cutaneous or mucous membrane squamous cell carcinoma. Clinical findings at presentation included best-corrected visual acuity), tumor laterality, tumor multiplicity, tissues involved (bulbar conjunctiva, forniceal conjunctiva, tarsal conjunctiva, plica semilunaris, caruncle, cornea, eyelid, and orbit), quadrant or location involved (superior, temporal, inferior, nasal, diffuse), largest tumor basal diameter, number of clock hours involved, tumor configuraton (flat, dome-shaped), lesion color, feeder and intrinsic vessels, leukoplakia, and internal pigment. The tumor configuration was considered flat if there was a flat surface of ≤1 mm thickness, whereas the tumors were considered dome-shaped if the mass gradually increased in thickness from the margin to a central apex and were >1 mm thickness centrally.
The number of months of topical IFNα2b therapy were recorded. At each follow-up examination, features were recorded regarding best-corrected visual acuity, tumor basal diameter, tissue involvement, and interferon-induced toxicity. Treatment outcomes included tumor control (complete, partial, or no response), recurrence, treatment for recurrence, metastasis, and death. Complete response was defined as complete tumor regression with total disappearance of tumor. Partial response was defined as tumor regression of less than 100%. No response was defined as no visible change following therapy. Recurrence was defined as reappearance of tumor at the primary tumor location after complete resolution following topical IFNα2b. Additional treatment required for tumor control after primary topical IFNα2b was noted. Spread to regional lymph nodes was assessed by history and palpation of preauricular, submental, submandibular, and cervical lymph nodes at each visit. Distant metastasis and death per the general medical physician were recorded.
Demographics, clinical features, and outcomes were compared by tumor configuration (flat vs. dome-shaped) using Fisher's exact test, Chi-squared test, and Mann Whitney U test. A P value <0.05 was considered significant.
Results
Of the 236 consecutive patients with clinically evident OSSN evaluated and managed on the Ocular Oncology Service, Wills Eye Hospital, during this time period, there were 64 tumors in 63 eyes of 63 patients that met inclusion criteria for this study. Tumors were classified according to surface configuration (flat (thin) (n = 15, 23%) vs. dome-shaped (thick) (n = 49, 77%)).
The patient demographic features are listed in Table 1. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with older mean patient age (62 vs. 70 years, P = 0.04) and greater frequency of smoking (13% vs. 42%, P = 0.04). There was no difference regarding patient race, sex, or Fitzpatrick Skin Type, autoimmune disease, immunosuppression, medical history of squamous neoplasia elsewhere, and tumor laterality and multiplicity.
Table 1 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases of 63 Patients. Demographic features
Demographic Features Flat [Tis] (n=15 patients) [n (%)] Dome-shaped [T3] (n=48 patients) [n (%)] P Total (n=63 patients) [n (%)]
Age (years)
Mean (median, range) 62 (61, 45-85) 70 (68, 30-97) 0.04 68 (64, 30-97)
Race
Caucasian 14 (93) 45 (94) 0.67 59 (94)
African American 1 (7) 1 (2) 2 (3)
Hispanic 0 (0) 1 (2) 1 (2)
Asian 0 (0) 1 (2) 1 (2)
Sex
Male 8 (53) 27 (56) 0.84 35 (56)
Female 7 (47) 21 (44) 28 (44)
Fitzpatrick Skin Type
I 4 (27) 17 (35) 0.73 21 (33)
II 9 (60) 23 (48) 32 (51)
III 1 (7) 5 (10) 6 (10)
IV 0 (0) 2 (4) 2 (3)
V 0 (0) 0 (0) 0 (0)
VI 1 (7) 1 (2) 2 (3)
Smoking History
Yes 2 (13) 20 (42) 0.04 22 (34)
No 13 (87) 28 (58) 42 (66)
Medical History - Autoimmune
Celiac 0 (0) 1 (2) 0.77 1 (2)
Ocular cicatricial pemphigoid 0 (0) 1 (2) 0.77 1 (2)
Psoriatic arthritis 1 (7) 0 (0) 0.23 1 (2)
Rheumatoid arthritis* 0 (0) 1 (2) 0.77 1 (2)
Sjögren’s syndrome* 0 (0) 1 (2) 0.77 1 (2)
Thyroiditis 0 (0) 1 (2) 0.77 1 (2)
Medical History - Immunosuppression
Chronic systemic corticosteroids 1 (7) 2 (4) 0.56 3 (5)
Chronic systemic immunosuppressants 1 (7) 2 (4) 0.56 3 (5)
Chronic topical corticosteroids 0 (0) 1 (2) 0.99 1 (2)
Organ transplant 0 (0) 1 (2) 0.99 1 (2)
Corneal graft 0 (0) 2 (4) 0.99 2 (3)
HPV history 1 (7) 1 (2) 0.42 2 (3)
Medical History - SCC History
Skin SCC 2 (13) 6 (13) 0.93 8 (13)
Mucosal SCC** 0 (0) 2 (4) 0.99 2 (3)
Laterality
Right 4 (27) 25 (52) 0.40 29 (46)
Left 11 (73) 23 (48) 34 (54)
Multiplicity of tumors
Single 15 (100) 47 (98) 0.99 62 (98)
Multiple 0 (0) 1 (2) 1 (2)
HPV=Human papilloma virus, SCC=squamous cell carcinoma. Bold values indicate significant P. * There was one patient diagnosed with both rheumatoid arthritis and Sjögren’s syndrome. **There was one case of oropharyngeal SCC and one case of rectal SCC
The tumor features are listed in Table 2. At presentation, there was no evidence of lymph node or distant metastatic disease. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with greater corneal involvement (7%% vs. 82%, P < 0.001), greater mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and greater mean clock hour involvement (1.9 vs. 4.1, P = 0.002). There was no difference in tumor quadrant, growth pattern, color, vascularity, or additional features.
Table 2 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Tumor characteristics
Tumor Characteristics Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
Tissue involved
Bulbar 13 (87) 41 (84) 0.78 54 (84)
Fornix 0 (0) 9 (18) 0.07 9 (14)
Tarsus 2 (13) 6 (12) 0.91 8 (13)
Plica semilunaris 0 (0) 1 (2) 0.99 1 (2)
Caruncle 0 (0) 2 (4) 0.99 2 (3)
Cornea 1 (7%) 40 (82) <0.001 41 (64)
Eyelid 0 (0) 2 (4) 0.99 2 (3)
Orbit 0 (0) 0 (0) NA 0 (0)
Quadrant involved
Superior 1 (7) 4 (8) 0.97 5 (8)
Temporal 3 (20) 10 (20) 13 (20)
Inferior 2 (13) 9 (18) 11 (17)
Nasal 9 (60) 25 (51) 34 (53)
Diffuse 0 (0) 1 (2) 1 (2)
Tumor Size
Largest basal diameter (mm) Mean (median, range) 5.5 (5.0, 1.0-12.0) 12.4 (10.0, 1.5-60.0) 0.001 10.8 (8.2, 1.0-60.0)
Number of clock hours involved Mean (median, range) 1.9 (2.0, 1.0-5.0) 4.1 (3.0, 1.0-12.0) 0.002 3.6 (3.0, 1.0-12.0)
Tumor Color
Pink 2 (13) 6 (12) 0.99 8 (12)
Yellow 10 (67) 34 (69) 44 (69)
White 3 (20) 9 (18) 12 (19)
Tumor Vascularity
Intrinsic vessels 8 (53) 28 (57) 0.80 36 (56)
Feeder vessels 6 (40) 18 (37) 0.82 24 (37)
Additional features
Leukoplakia 5 (33) 8 (16) 0.15 13 (20)
Internal cysts 1 (7) 0 (0) 0.23 1 (2)
Internal pigment 0 (0) 0 (0) NA 0 (0)
Bold values indicate significant P
Topical IFNα2b at a dose of 1 million IU/mL administered 4 times daily was used as primary monotherapy for all patients. The tumor response is listed in Table 3. There was no difference in percentage of patients lost to follow-up (7% vs. 2%, P = 0.42) or mean follow-up time (22.2 vs. 23.1 months, P = 0.87). A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with longer mean duration of IFNα2b monotherapy for tumor control (3.7 vs. 6.3 months, P = 0.002). There was no difference in complete tumor response (93% vs. 96%, (P = 0.65), partial response (7% vs. 2%), or no response (0% vs. 2%) (P = 0.54) [Fig. 1]. The single patient with no response had prior corneal graft and received topical IFNα2b with no improvement, and later required subconjunctival IFNα2b injection. There was no difference regarding mean time to complete response (5.0 vs. 6.1 months, P = 0.25). Following initial response, there was no difference in tumor recurrence (7% vs. 2%, P = 0.41). Regarding local treatment side effects, flat tumors had more frequent follicular reaction (20% vs. 2%, P = 0.04). There was no difference in ocular surface irritation or corneal epithelial defect. There were no patients who developed metastatic disease or death.
Table 3 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Outcomes
Outcomes Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
No follow-up 1 (7) 1 (2) 0.42 2 (3)
Tumor response n=14 n=48 n=62
Complete 13 (93) 46 (96) 0.54 59 (95)
Partial 1 (7)* 1 (2)** 2 (3)
No response 0 (0) 1 (2)*** 1 (2)
n=14 n=47 n=61
Recurrence after initial response 1 (7) 1 (2) 0.41 2 (3)
Additional treatment needed for complete response 1 (7) 6 (13) 0.68 7 (11)
Topical mitomycin C 0 (0) 1 (2) 0.99 1 (2)
Surgical excision 1 (7) 5 (9) 0.99 6 (10)
Local treatment side effects
Follicular reaction 3 (20) 1 (2) 0.04 4 (6)
Irritation 0 (0) 1 (2) 0.99 1 (2)
Corneal epithelial defect 0 (0) 1 (2) 0.99 2 (3)
Systemic outcomes
Metastasis 0 (0) 0 (0) NA 0 (0)
Death 0 (0) 0 (0) NA 0 (0)
Total duration of interferon alpha-2b therapy (months)
Mean (median, range) 3.7 (3.0, 0.5-7.0) 6.3 (6.0, 1.0-13.0) 0.002 5.7 (5.0, 0.5-13.0)
Time to complete response (months)
Mean (median, range) 5.0 (3.8, 1.0-11.5) 6.1 (5.4, 1.3-17.8) 0.25 5.8 (5.0, 1.0-17.8)
Follow-up time (months) n=14 n=48 n=62
Mean (median, range) 22.2 (14.3, 2.9-63.1) 23.1 (13.9, 1.3-114.6) 0.87 23.0 (14.4, 1.3-114.6)
Bold values indicate significant P. * Patient lost to follow-up after 7 months of therapy due to liver transplant. ** Patient stopped interferon alpha-2b after 1 month due to ocular surface discomfort and was lost to follow-up. *** Patient elected not to continue treatment after secondary treatment was advised
Figure 1 Treatment of ocular surface squamous neoplasia (OSSN) using topical interferon alpha-2b (IFNa2b) monotherapy. Flat vascular OSSN in a 76-year-old female (a) before and (b) after 4 months of IFNa2b monotherapy. Dome-shaped OSSN in a 57-year-old female (c) before and (d) after 8 months of IFNa2b monotherapy
Discussion
A recent report of 5002 conjunctival tumors from an ocular oncology center revealed that premalignant/malignant squamous neoplasia (OSSN) represented 729 (15%) of all cases, mostly with diagnoses of conjunctival intraepithelial neoplasia (CIN) (n = 275 tumors) or squamous cell carcinoma (SCC) (n = 440 tumors).[7] In that analysis, CIN or SCC was most often noted at the corneoscleral limbus (575/715, 80%), located nasally (269/715, 38%) or temporally (285/715, 40%), and appearing as a lump/swelling to the patient (434/715, 61%).
In 2012, Shah et al. reported the results of topical v for OSSN in 23 cases based on the 7th edition AJCC classification and noted that complete control was achieved in 83% of cases, specifically 67% of those labeled as Tis and 85% of the T3 group.[8] In that analysis there were no patients with T1, T2, or T4, as found in our current study. Further investigation of topical or injection IFNα2b for OSSN revealed applications for immunoreduction of giant OSSN, and immunoprevention in immunosuppressed patients, especially those with human immunodeficiency virus (HIV) or organ transplant who are at risk to have numerous and multifocal OSSN.[910] Galor et al. compared the topical dose of 1 million IU/ml to 3 million IU/mL IFNα2b and found no difference in tumor response, treatment duration, recurrence, or adverse effects.[11]
Since the above publications, the AJCC has been updated to the 8th edition. However, classification requires tumor biopsy and histopathologic analysis, but in this current era of topical therapies, clinicians often avoid biopsy when starting topical therapies if the diagnosis is clinical evident. Thus, AJCC classification is not possible for clinicians using purely topical therapies. In this report, we accommodate AJCC 8th edition classification by inferring that flat tumor configuration with no corneal component might serve as a surrogate for Tis and dome-shaped as T1, T2, T3, or T4.
In this analysis, we were able to provide a comparative analysis of tumor control with topical IFNα2b monotherapy without the need for biopsy. We found important differences in clinical features in that dome-shaped tumors occurred in older mean patient age (62 vs. 70 years, P = 0.04), with greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (0% vs. 84%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean clock hour extent (1.9 vs. 4.3, P = 0.002). To achieve control with topical IFNα2b, dome-shaped tumors tumors required greater mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002) for equivalent complete tumor control (93% vs. 96%, P = 0.65).
There are limitations to this study that should be considered. The data was a retrospective collection with inherent biases and drawbacks. Additionally, the cohort size was relatively small at 64 cases, resulting in limited statistical power, but due to the rarity of this malignancy and strict inclusion criteria of primary treatment with topical IFNα2b monotherapy only, our data represents pure data with few conflicting events. We recognize that precise AJCC classification could not be performed without histopathologic anaylsis, and microscopic invasion of the basement membrane in the case of flat tumor could have been missed. Nevertheless, with excellent tumor control for both flat and dome-shaped tumor, biopsy would not likely have changed our main study conclusion. Perhaps further studies could evaluate outcomes based on clinical imaging such as anterior segment optical coherence tomography or ultrasound biomicroscopy. Lastly, further follow-up with larger cohort in the future could potentially verify our observations.
Most previous studies on this topic have included pretreatment biopsy for diagnostic and staging confirmation, but that interferes with the ability to promptly employ some topical therapies and adds a confounding factor of the amount of tumor surgically excised versus the remnant of tumor left for treatment with topical therapy. Hence, we chose to avoid biopsy as this is consistent with how most clinicians currently approach clinically-evident OSSN, especially when starting topical therapy. Thus our results reflect the impact of topical IFNα2b monotherapy for the entire OSSN without the need for biopsy.
Conclusion
In conclusion, based on tumor configuration of OSSN, overall tumor control is 95% and does not differ when comparing flat to dome-shaped tumors. In addition, dome-shaped tumors required longer duration of therapy and demonstrated no greater recurrence upon discontinuation of the medication. We conclude that topical IFNα2b monotherapy is highly effective for the treatment of conjunctival OSSN, whether or not the tumor is flat or dome-shaped.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | INTERFERON ALFA-2B | DrugsGivenReaction | CC BY-NC-SA | 33595473 | 19,031,058 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Eye irritation'. | Primary treatment of ocular surface squamous neoplasia with topical interferon alpha-2b: Comparative analysis of outcomes based on original tumor configuration.
The aim of this study was to evaluate tumor control of OSSN with topical IFNα2b alone based on tumor configuration (flat versus (vs.) dome-shaped).
Retrospective, nonrandomized, interventional cohort study on 64 consecutive tumors in 63 patients with OSSN treated with topical IFNα2b. Topical IFNα2b (1 million international units/cc) was compounded and provided by the Thomas Jefferson University Hospital Pharmacy to be refrigerated and applied 4 times daily until biomicroscopic evidence of tumor resolution was observed.
The tumor configuration was flat (n = 15, 23%) or dome-shaped (n = 49, 77%). A comparison (flat vs. dome-shaped) revealed dome-shaped with older mean patient age at presentation (62 vs. 70 years, P = 0.04), greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (7% vs. 82%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean thickness (1.9 vs. 4.3, P = 0.002), and longer mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002). There was no difference in mean follow-up time (22.2 vs 23.1 months) or time to complete response (5.0 vs. 6.1 months). There was no difference in achievement of complete tumor control with IFNα2b alone (93% vs. 96%). There were no cases with metastasis or death.
Topical IFNα2b alone shows excellent overall tumor control of 95% with no difference in efficacy based on tumor configuration.
Ocular surface squamous neoplasia (OSSN) is an umbrella term referring to the spectrum of squamous epithelial malignancy that can occur on the ocular surface, from in situ mild dysplasia to invasive epithelial malignant tumors. Based on the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study of 566,401 individuals aged 50-71 years, the incidence of OSSN was 8.4 per million persons, and found to be greater incidence in males (10.3 per million) and age >60 years (10.0 per million).[1] The management of this malignancy involves surgical and non-surgical alternatives, using topical or injection chemotherapy or immunotherapy. Several publications have explored the role of topical interferon alpha 2-B (IFNα2b) for tumor management.[123] A matched comparative analysis (IFNα2b (topical and injections) versus (vs.) surgery) for OSSN therapy revealed no difference in the recurrence rate (3% vs. 5%)[4] and non-significant equivalent cost for the full course of the two alternatives ($2831 vs $3528 US dollars (Medicare allowable charges)).[5] Thus, topical and injection IFNα2b for OSSN remains an important therapeutic alternative to surgery for affected patients.
Herein, we specifically focus on the role of topical IFNα2b monotherapy in the management of OSSN. In this analysis, we explore tumor control with topical IFNα2b based on tumor configuration (flat versus (vs.) dome-shaped). Many clinicians using topical therapies apply the medications based on classic tumor features and without the need for tumor biopsy, to spare the patient surgical intervention. Thus, tumor grouping by the American Joint Committee on Cancer (AJCC) Classification is not possible, as histopathology evaluation of tumor depth (in situ vs. deeper) is not available. However, one might speculate that tumor configuration as flat could serve as a surrogate for Tis and configuration as dome-shaped could represent T1, T2, T3, or T4 based on tumor basal dimension and adjacent tissue involvement as proposed by the AJCC.[6] Herein, we explore outcomes of topical IFNα2b based on practical tumor configuration, whether the tumor is thin (flat) or thick (dome-shaped).
Methods
The medical records of all patients with clinically-evident OSSN diagnosed and managed on the Ocular Oncology Service at Wills Eye Hospital, Philadelphia USA, between October 4, 2005, and January 28, 2019 were retrospectively reviewed. Patients were included if primary treatment for OSSN consisted only of topical IFNα2b monotherapy. Patients who received treatment prior to referral, or those who received subconjunctival injection of IFNα2b or were treated with prophylactic IFNα2b were excluded. The treatment protocol included use of IFNα2b (Intron-A, Schering-Plough, London UK) in a topical formulation of 1 million international units (IU)/mL compounded by Thomas Jefferson University Hospital Pharmacy, Philadelphia USA, and stored in refrigeration, avoiding disturbance or shaking of the bottle. The eye drops were administered 4 times daily until 1 month beyond clinical evidence of complete tumor resolution or until the time a secondary treatment was deemed necessary due to poor response. The response to treatment was monitored every 3 to 6 months and the duration of treatment was modified on the basis of tumor response. This study was approved by the Institutional Review Board of Wills Eye Hospital, Philadelphia USA and adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all patients.
All patients were examined by a trained ocular oncologist (CLS, SEL) with slit-lamp biomicroscopy, documentation on detailed, large conjunctival drawings, and with photographic documentation. The demographic data included age, race, sex, and Fitzpatrick skin type. Past medical history included risk factors of smoking status, autoimmune condition, chronic use (>6 months) of topical or systemic corticosteroids or other immunosuppressive medications, organ transplant, corneal graft, human papillomavirus (HPV) infection, human immunodeficiency virus infection, and cutaneous or mucous membrane squamous cell carcinoma. Clinical findings at presentation included best-corrected visual acuity), tumor laterality, tumor multiplicity, tissues involved (bulbar conjunctiva, forniceal conjunctiva, tarsal conjunctiva, plica semilunaris, caruncle, cornea, eyelid, and orbit), quadrant or location involved (superior, temporal, inferior, nasal, diffuse), largest tumor basal diameter, number of clock hours involved, tumor configuraton (flat, dome-shaped), lesion color, feeder and intrinsic vessels, leukoplakia, and internal pigment. The tumor configuration was considered flat if there was a flat surface of ≤1 mm thickness, whereas the tumors were considered dome-shaped if the mass gradually increased in thickness from the margin to a central apex and were >1 mm thickness centrally.
The number of months of topical IFNα2b therapy were recorded. At each follow-up examination, features were recorded regarding best-corrected visual acuity, tumor basal diameter, tissue involvement, and interferon-induced toxicity. Treatment outcomes included tumor control (complete, partial, or no response), recurrence, treatment for recurrence, metastasis, and death. Complete response was defined as complete tumor regression with total disappearance of tumor. Partial response was defined as tumor regression of less than 100%. No response was defined as no visible change following therapy. Recurrence was defined as reappearance of tumor at the primary tumor location after complete resolution following topical IFNα2b. Additional treatment required for tumor control after primary topical IFNα2b was noted. Spread to regional lymph nodes was assessed by history and palpation of preauricular, submental, submandibular, and cervical lymph nodes at each visit. Distant metastasis and death per the general medical physician were recorded.
Demographics, clinical features, and outcomes were compared by tumor configuration (flat vs. dome-shaped) using Fisher's exact test, Chi-squared test, and Mann Whitney U test. A P value <0.05 was considered significant.
Results
Of the 236 consecutive patients with clinically evident OSSN evaluated and managed on the Ocular Oncology Service, Wills Eye Hospital, during this time period, there were 64 tumors in 63 eyes of 63 patients that met inclusion criteria for this study. Tumors were classified according to surface configuration (flat (thin) (n = 15, 23%) vs. dome-shaped (thick) (n = 49, 77%)).
The patient demographic features are listed in Table 1. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with older mean patient age (62 vs. 70 years, P = 0.04) and greater frequency of smoking (13% vs. 42%, P = 0.04). There was no difference regarding patient race, sex, or Fitzpatrick Skin Type, autoimmune disease, immunosuppression, medical history of squamous neoplasia elsewhere, and tumor laterality and multiplicity.
Table 1 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases of 63 Patients. Demographic features
Demographic Features Flat [Tis] (n=15 patients) [n (%)] Dome-shaped [T3] (n=48 patients) [n (%)] P Total (n=63 patients) [n (%)]
Age (years)
Mean (median, range) 62 (61, 45-85) 70 (68, 30-97) 0.04 68 (64, 30-97)
Race
Caucasian 14 (93) 45 (94) 0.67 59 (94)
African American 1 (7) 1 (2) 2 (3)
Hispanic 0 (0) 1 (2) 1 (2)
Asian 0 (0) 1 (2) 1 (2)
Sex
Male 8 (53) 27 (56) 0.84 35 (56)
Female 7 (47) 21 (44) 28 (44)
Fitzpatrick Skin Type
I 4 (27) 17 (35) 0.73 21 (33)
II 9 (60) 23 (48) 32 (51)
III 1 (7) 5 (10) 6 (10)
IV 0 (0) 2 (4) 2 (3)
V 0 (0) 0 (0) 0 (0)
VI 1 (7) 1 (2) 2 (3)
Smoking History
Yes 2 (13) 20 (42) 0.04 22 (34)
No 13 (87) 28 (58) 42 (66)
Medical History - Autoimmune
Celiac 0 (0) 1 (2) 0.77 1 (2)
Ocular cicatricial pemphigoid 0 (0) 1 (2) 0.77 1 (2)
Psoriatic arthritis 1 (7) 0 (0) 0.23 1 (2)
Rheumatoid arthritis* 0 (0) 1 (2) 0.77 1 (2)
Sjögren’s syndrome* 0 (0) 1 (2) 0.77 1 (2)
Thyroiditis 0 (0) 1 (2) 0.77 1 (2)
Medical History - Immunosuppression
Chronic systemic corticosteroids 1 (7) 2 (4) 0.56 3 (5)
Chronic systemic immunosuppressants 1 (7) 2 (4) 0.56 3 (5)
Chronic topical corticosteroids 0 (0) 1 (2) 0.99 1 (2)
Organ transplant 0 (0) 1 (2) 0.99 1 (2)
Corneal graft 0 (0) 2 (4) 0.99 2 (3)
HPV history 1 (7) 1 (2) 0.42 2 (3)
Medical History - SCC History
Skin SCC 2 (13) 6 (13) 0.93 8 (13)
Mucosal SCC** 0 (0) 2 (4) 0.99 2 (3)
Laterality
Right 4 (27) 25 (52) 0.40 29 (46)
Left 11 (73) 23 (48) 34 (54)
Multiplicity of tumors
Single 15 (100) 47 (98) 0.99 62 (98)
Multiple 0 (0) 1 (2) 1 (2)
HPV=Human papilloma virus, SCC=squamous cell carcinoma. Bold values indicate significant P. * There was one patient diagnosed with both rheumatoid arthritis and Sjögren’s syndrome. **There was one case of oropharyngeal SCC and one case of rectal SCC
The tumor features are listed in Table 2. At presentation, there was no evidence of lymph node or distant metastatic disease. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with greater corneal involvement (7%% vs. 82%, P < 0.001), greater mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and greater mean clock hour involvement (1.9 vs. 4.1, P = 0.002). There was no difference in tumor quadrant, growth pattern, color, vascularity, or additional features.
Table 2 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Tumor characteristics
Tumor Characteristics Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
Tissue involved
Bulbar 13 (87) 41 (84) 0.78 54 (84)
Fornix 0 (0) 9 (18) 0.07 9 (14)
Tarsus 2 (13) 6 (12) 0.91 8 (13)
Plica semilunaris 0 (0) 1 (2) 0.99 1 (2)
Caruncle 0 (0) 2 (4) 0.99 2 (3)
Cornea 1 (7%) 40 (82) <0.001 41 (64)
Eyelid 0 (0) 2 (4) 0.99 2 (3)
Orbit 0 (0) 0 (0) NA 0 (0)
Quadrant involved
Superior 1 (7) 4 (8) 0.97 5 (8)
Temporal 3 (20) 10 (20) 13 (20)
Inferior 2 (13) 9 (18) 11 (17)
Nasal 9 (60) 25 (51) 34 (53)
Diffuse 0 (0) 1 (2) 1 (2)
Tumor Size
Largest basal diameter (mm) Mean (median, range) 5.5 (5.0, 1.0-12.0) 12.4 (10.0, 1.5-60.0) 0.001 10.8 (8.2, 1.0-60.0)
Number of clock hours involved Mean (median, range) 1.9 (2.0, 1.0-5.0) 4.1 (3.0, 1.0-12.0) 0.002 3.6 (3.0, 1.0-12.0)
Tumor Color
Pink 2 (13) 6 (12) 0.99 8 (12)
Yellow 10 (67) 34 (69) 44 (69)
White 3 (20) 9 (18) 12 (19)
Tumor Vascularity
Intrinsic vessels 8 (53) 28 (57) 0.80 36 (56)
Feeder vessels 6 (40) 18 (37) 0.82 24 (37)
Additional features
Leukoplakia 5 (33) 8 (16) 0.15 13 (20)
Internal cysts 1 (7) 0 (0) 0.23 1 (2)
Internal pigment 0 (0) 0 (0) NA 0 (0)
Bold values indicate significant P
Topical IFNα2b at a dose of 1 million IU/mL administered 4 times daily was used as primary monotherapy for all patients. The tumor response is listed in Table 3. There was no difference in percentage of patients lost to follow-up (7% vs. 2%, P = 0.42) or mean follow-up time (22.2 vs. 23.1 months, P = 0.87). A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with longer mean duration of IFNα2b monotherapy for tumor control (3.7 vs. 6.3 months, P = 0.002). There was no difference in complete tumor response (93% vs. 96%, (P = 0.65), partial response (7% vs. 2%), or no response (0% vs. 2%) (P = 0.54) [Fig. 1]. The single patient with no response had prior corneal graft and received topical IFNα2b with no improvement, and later required subconjunctival IFNα2b injection. There was no difference regarding mean time to complete response (5.0 vs. 6.1 months, P = 0.25). Following initial response, there was no difference in tumor recurrence (7% vs. 2%, P = 0.41). Regarding local treatment side effects, flat tumors had more frequent follicular reaction (20% vs. 2%, P = 0.04). There was no difference in ocular surface irritation or corneal epithelial defect. There were no patients who developed metastatic disease or death.
Table 3 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Outcomes
Outcomes Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
No follow-up 1 (7) 1 (2) 0.42 2 (3)
Tumor response n=14 n=48 n=62
Complete 13 (93) 46 (96) 0.54 59 (95)
Partial 1 (7)* 1 (2)** 2 (3)
No response 0 (0) 1 (2)*** 1 (2)
n=14 n=47 n=61
Recurrence after initial response 1 (7) 1 (2) 0.41 2 (3)
Additional treatment needed for complete response 1 (7) 6 (13) 0.68 7 (11)
Topical mitomycin C 0 (0) 1 (2) 0.99 1 (2)
Surgical excision 1 (7) 5 (9) 0.99 6 (10)
Local treatment side effects
Follicular reaction 3 (20) 1 (2) 0.04 4 (6)
Irritation 0 (0) 1 (2) 0.99 1 (2)
Corneal epithelial defect 0 (0) 1 (2) 0.99 2 (3)
Systemic outcomes
Metastasis 0 (0) 0 (0) NA 0 (0)
Death 0 (0) 0 (0) NA 0 (0)
Total duration of interferon alpha-2b therapy (months)
Mean (median, range) 3.7 (3.0, 0.5-7.0) 6.3 (6.0, 1.0-13.0) 0.002 5.7 (5.0, 0.5-13.0)
Time to complete response (months)
Mean (median, range) 5.0 (3.8, 1.0-11.5) 6.1 (5.4, 1.3-17.8) 0.25 5.8 (5.0, 1.0-17.8)
Follow-up time (months) n=14 n=48 n=62
Mean (median, range) 22.2 (14.3, 2.9-63.1) 23.1 (13.9, 1.3-114.6) 0.87 23.0 (14.4, 1.3-114.6)
Bold values indicate significant P. * Patient lost to follow-up after 7 months of therapy due to liver transplant. ** Patient stopped interferon alpha-2b after 1 month due to ocular surface discomfort and was lost to follow-up. *** Patient elected not to continue treatment after secondary treatment was advised
Figure 1 Treatment of ocular surface squamous neoplasia (OSSN) using topical interferon alpha-2b (IFNa2b) monotherapy. Flat vascular OSSN in a 76-year-old female (a) before and (b) after 4 months of IFNa2b monotherapy. Dome-shaped OSSN in a 57-year-old female (c) before and (d) after 8 months of IFNa2b monotherapy
Discussion
A recent report of 5002 conjunctival tumors from an ocular oncology center revealed that premalignant/malignant squamous neoplasia (OSSN) represented 729 (15%) of all cases, mostly with diagnoses of conjunctival intraepithelial neoplasia (CIN) (n = 275 tumors) or squamous cell carcinoma (SCC) (n = 440 tumors).[7] In that analysis, CIN or SCC was most often noted at the corneoscleral limbus (575/715, 80%), located nasally (269/715, 38%) or temporally (285/715, 40%), and appearing as a lump/swelling to the patient (434/715, 61%).
In 2012, Shah et al. reported the results of topical v for OSSN in 23 cases based on the 7th edition AJCC classification and noted that complete control was achieved in 83% of cases, specifically 67% of those labeled as Tis and 85% of the T3 group.[8] In that analysis there were no patients with T1, T2, or T4, as found in our current study. Further investigation of topical or injection IFNα2b for OSSN revealed applications for immunoreduction of giant OSSN, and immunoprevention in immunosuppressed patients, especially those with human immunodeficiency virus (HIV) or organ transplant who are at risk to have numerous and multifocal OSSN.[910] Galor et al. compared the topical dose of 1 million IU/ml to 3 million IU/mL IFNα2b and found no difference in tumor response, treatment duration, recurrence, or adverse effects.[11]
Since the above publications, the AJCC has been updated to the 8th edition. However, classification requires tumor biopsy and histopathologic analysis, but in this current era of topical therapies, clinicians often avoid biopsy when starting topical therapies if the diagnosis is clinical evident. Thus, AJCC classification is not possible for clinicians using purely topical therapies. In this report, we accommodate AJCC 8th edition classification by inferring that flat tumor configuration with no corneal component might serve as a surrogate for Tis and dome-shaped as T1, T2, T3, or T4.
In this analysis, we were able to provide a comparative analysis of tumor control with topical IFNα2b monotherapy without the need for biopsy. We found important differences in clinical features in that dome-shaped tumors occurred in older mean patient age (62 vs. 70 years, P = 0.04), with greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (0% vs. 84%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean clock hour extent (1.9 vs. 4.3, P = 0.002). To achieve control with topical IFNα2b, dome-shaped tumors tumors required greater mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002) for equivalent complete tumor control (93% vs. 96%, P = 0.65).
There are limitations to this study that should be considered. The data was a retrospective collection with inherent biases and drawbacks. Additionally, the cohort size was relatively small at 64 cases, resulting in limited statistical power, but due to the rarity of this malignancy and strict inclusion criteria of primary treatment with topical IFNα2b monotherapy only, our data represents pure data with few conflicting events. We recognize that precise AJCC classification could not be performed without histopathologic anaylsis, and microscopic invasion of the basement membrane in the case of flat tumor could have been missed. Nevertheless, with excellent tumor control for both flat and dome-shaped tumor, biopsy would not likely have changed our main study conclusion. Perhaps further studies could evaluate outcomes based on clinical imaging such as anterior segment optical coherence tomography or ultrasound biomicroscopy. Lastly, further follow-up with larger cohort in the future could potentially verify our observations.
Most previous studies on this topic have included pretreatment biopsy for diagnostic and staging confirmation, but that interferes with the ability to promptly employ some topical therapies and adds a confounding factor of the amount of tumor surgically excised versus the remnant of tumor left for treatment with topical therapy. Hence, we chose to avoid biopsy as this is consistent with how most clinicians currently approach clinically-evident OSSN, especially when starting topical therapy. Thus our results reflect the impact of topical IFNα2b monotherapy for the entire OSSN without the need for biopsy.
Conclusion
In conclusion, based on tumor configuration of OSSN, overall tumor control is 95% and does not differ when comparing flat to dome-shaped tumors. In addition, dome-shaped tumors required longer duration of therapy and demonstrated no greater recurrence upon discontinuation of the medication. We conclude that topical IFNα2b monotherapy is highly effective for the treatment of conjunctival OSSN, whether or not the tumor is flat or dome-shaped.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | INTERFERON ALFA-2B | DrugsGivenReaction | CC BY-NC-SA | 33595473 | 19,031,058 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Incorrect route of product administration'. | Primary treatment of ocular surface squamous neoplasia with topical interferon alpha-2b: Comparative analysis of outcomes based on original tumor configuration.
The aim of this study was to evaluate tumor control of OSSN with topical IFNα2b alone based on tumor configuration (flat versus (vs.) dome-shaped).
Retrospective, nonrandomized, interventional cohort study on 64 consecutive tumors in 63 patients with OSSN treated with topical IFNα2b. Topical IFNα2b (1 million international units/cc) was compounded and provided by the Thomas Jefferson University Hospital Pharmacy to be refrigerated and applied 4 times daily until biomicroscopic evidence of tumor resolution was observed.
The tumor configuration was flat (n = 15, 23%) or dome-shaped (n = 49, 77%). A comparison (flat vs. dome-shaped) revealed dome-shaped with older mean patient age at presentation (62 vs. 70 years, P = 0.04), greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (7% vs. 82%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean thickness (1.9 vs. 4.3, P = 0.002), and longer mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002). There was no difference in mean follow-up time (22.2 vs 23.1 months) or time to complete response (5.0 vs. 6.1 months). There was no difference in achievement of complete tumor control with IFNα2b alone (93% vs. 96%). There were no cases with metastasis or death.
Topical IFNα2b alone shows excellent overall tumor control of 95% with no difference in efficacy based on tumor configuration.
Ocular surface squamous neoplasia (OSSN) is an umbrella term referring to the spectrum of squamous epithelial malignancy that can occur on the ocular surface, from in situ mild dysplasia to invasive epithelial malignant tumors. Based on the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study of 566,401 individuals aged 50-71 years, the incidence of OSSN was 8.4 per million persons, and found to be greater incidence in males (10.3 per million) and age >60 years (10.0 per million).[1] The management of this malignancy involves surgical and non-surgical alternatives, using topical or injection chemotherapy or immunotherapy. Several publications have explored the role of topical interferon alpha 2-B (IFNα2b) for tumor management.[123] A matched comparative analysis (IFNα2b (topical and injections) versus (vs.) surgery) for OSSN therapy revealed no difference in the recurrence rate (3% vs. 5%)[4] and non-significant equivalent cost for the full course of the two alternatives ($2831 vs $3528 US dollars (Medicare allowable charges)).[5] Thus, topical and injection IFNα2b for OSSN remains an important therapeutic alternative to surgery for affected patients.
Herein, we specifically focus on the role of topical IFNα2b monotherapy in the management of OSSN. In this analysis, we explore tumor control with topical IFNα2b based on tumor configuration (flat versus (vs.) dome-shaped). Many clinicians using topical therapies apply the medications based on classic tumor features and without the need for tumor biopsy, to spare the patient surgical intervention. Thus, tumor grouping by the American Joint Committee on Cancer (AJCC) Classification is not possible, as histopathology evaluation of tumor depth (in situ vs. deeper) is not available. However, one might speculate that tumor configuration as flat could serve as a surrogate for Tis and configuration as dome-shaped could represent T1, T2, T3, or T4 based on tumor basal dimension and adjacent tissue involvement as proposed by the AJCC.[6] Herein, we explore outcomes of topical IFNα2b based on practical tumor configuration, whether the tumor is thin (flat) or thick (dome-shaped).
Methods
The medical records of all patients with clinically-evident OSSN diagnosed and managed on the Ocular Oncology Service at Wills Eye Hospital, Philadelphia USA, between October 4, 2005, and January 28, 2019 were retrospectively reviewed. Patients were included if primary treatment for OSSN consisted only of topical IFNα2b monotherapy. Patients who received treatment prior to referral, or those who received subconjunctival injection of IFNα2b or were treated with prophylactic IFNα2b were excluded. The treatment protocol included use of IFNα2b (Intron-A, Schering-Plough, London UK) in a topical formulation of 1 million international units (IU)/mL compounded by Thomas Jefferson University Hospital Pharmacy, Philadelphia USA, and stored in refrigeration, avoiding disturbance or shaking of the bottle. The eye drops were administered 4 times daily until 1 month beyond clinical evidence of complete tumor resolution or until the time a secondary treatment was deemed necessary due to poor response. The response to treatment was monitored every 3 to 6 months and the duration of treatment was modified on the basis of tumor response. This study was approved by the Institutional Review Board of Wills Eye Hospital, Philadelphia USA and adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all patients.
All patients were examined by a trained ocular oncologist (CLS, SEL) with slit-lamp biomicroscopy, documentation on detailed, large conjunctival drawings, and with photographic documentation. The demographic data included age, race, sex, and Fitzpatrick skin type. Past medical history included risk factors of smoking status, autoimmune condition, chronic use (>6 months) of topical or systemic corticosteroids or other immunosuppressive medications, organ transplant, corneal graft, human papillomavirus (HPV) infection, human immunodeficiency virus infection, and cutaneous or mucous membrane squamous cell carcinoma. Clinical findings at presentation included best-corrected visual acuity), tumor laterality, tumor multiplicity, tissues involved (bulbar conjunctiva, forniceal conjunctiva, tarsal conjunctiva, plica semilunaris, caruncle, cornea, eyelid, and orbit), quadrant or location involved (superior, temporal, inferior, nasal, diffuse), largest tumor basal diameter, number of clock hours involved, tumor configuraton (flat, dome-shaped), lesion color, feeder and intrinsic vessels, leukoplakia, and internal pigment. The tumor configuration was considered flat if there was a flat surface of ≤1 mm thickness, whereas the tumors were considered dome-shaped if the mass gradually increased in thickness from the margin to a central apex and were >1 mm thickness centrally.
The number of months of topical IFNα2b therapy were recorded. At each follow-up examination, features were recorded regarding best-corrected visual acuity, tumor basal diameter, tissue involvement, and interferon-induced toxicity. Treatment outcomes included tumor control (complete, partial, or no response), recurrence, treatment for recurrence, metastasis, and death. Complete response was defined as complete tumor regression with total disappearance of tumor. Partial response was defined as tumor regression of less than 100%. No response was defined as no visible change following therapy. Recurrence was defined as reappearance of tumor at the primary tumor location after complete resolution following topical IFNα2b. Additional treatment required for tumor control after primary topical IFNα2b was noted. Spread to regional lymph nodes was assessed by history and palpation of preauricular, submental, submandibular, and cervical lymph nodes at each visit. Distant metastasis and death per the general medical physician were recorded.
Demographics, clinical features, and outcomes were compared by tumor configuration (flat vs. dome-shaped) using Fisher's exact test, Chi-squared test, and Mann Whitney U test. A P value <0.05 was considered significant.
Results
Of the 236 consecutive patients with clinically evident OSSN evaluated and managed on the Ocular Oncology Service, Wills Eye Hospital, during this time period, there were 64 tumors in 63 eyes of 63 patients that met inclusion criteria for this study. Tumors were classified according to surface configuration (flat (thin) (n = 15, 23%) vs. dome-shaped (thick) (n = 49, 77%)).
The patient demographic features are listed in Table 1. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with older mean patient age (62 vs. 70 years, P = 0.04) and greater frequency of smoking (13% vs. 42%, P = 0.04). There was no difference regarding patient race, sex, or Fitzpatrick Skin Type, autoimmune disease, immunosuppression, medical history of squamous neoplasia elsewhere, and tumor laterality and multiplicity.
Table 1 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases of 63 Patients. Demographic features
Demographic Features Flat [Tis] (n=15 patients) [n (%)] Dome-shaped [T3] (n=48 patients) [n (%)] P Total (n=63 patients) [n (%)]
Age (years)
Mean (median, range) 62 (61, 45-85) 70 (68, 30-97) 0.04 68 (64, 30-97)
Race
Caucasian 14 (93) 45 (94) 0.67 59 (94)
African American 1 (7) 1 (2) 2 (3)
Hispanic 0 (0) 1 (2) 1 (2)
Asian 0 (0) 1 (2) 1 (2)
Sex
Male 8 (53) 27 (56) 0.84 35 (56)
Female 7 (47) 21 (44) 28 (44)
Fitzpatrick Skin Type
I 4 (27) 17 (35) 0.73 21 (33)
II 9 (60) 23 (48) 32 (51)
III 1 (7) 5 (10) 6 (10)
IV 0 (0) 2 (4) 2 (3)
V 0 (0) 0 (0) 0 (0)
VI 1 (7) 1 (2) 2 (3)
Smoking History
Yes 2 (13) 20 (42) 0.04 22 (34)
No 13 (87) 28 (58) 42 (66)
Medical History - Autoimmune
Celiac 0 (0) 1 (2) 0.77 1 (2)
Ocular cicatricial pemphigoid 0 (0) 1 (2) 0.77 1 (2)
Psoriatic arthritis 1 (7) 0 (0) 0.23 1 (2)
Rheumatoid arthritis* 0 (0) 1 (2) 0.77 1 (2)
Sjögren’s syndrome* 0 (0) 1 (2) 0.77 1 (2)
Thyroiditis 0 (0) 1 (2) 0.77 1 (2)
Medical History - Immunosuppression
Chronic systemic corticosteroids 1 (7) 2 (4) 0.56 3 (5)
Chronic systemic immunosuppressants 1 (7) 2 (4) 0.56 3 (5)
Chronic topical corticosteroids 0 (0) 1 (2) 0.99 1 (2)
Organ transplant 0 (0) 1 (2) 0.99 1 (2)
Corneal graft 0 (0) 2 (4) 0.99 2 (3)
HPV history 1 (7) 1 (2) 0.42 2 (3)
Medical History - SCC History
Skin SCC 2 (13) 6 (13) 0.93 8 (13)
Mucosal SCC** 0 (0) 2 (4) 0.99 2 (3)
Laterality
Right 4 (27) 25 (52) 0.40 29 (46)
Left 11 (73) 23 (48) 34 (54)
Multiplicity of tumors
Single 15 (100) 47 (98) 0.99 62 (98)
Multiple 0 (0) 1 (2) 1 (2)
HPV=Human papilloma virus, SCC=squamous cell carcinoma. Bold values indicate significant P. * There was one patient diagnosed with both rheumatoid arthritis and Sjögren’s syndrome. **There was one case of oropharyngeal SCC and one case of rectal SCC
The tumor features are listed in Table 2. At presentation, there was no evidence of lymph node or distant metastatic disease. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with greater corneal involvement (7%% vs. 82%, P < 0.001), greater mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and greater mean clock hour involvement (1.9 vs. 4.1, P = 0.002). There was no difference in tumor quadrant, growth pattern, color, vascularity, or additional features.
Table 2 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Tumor characteristics
Tumor Characteristics Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
Tissue involved
Bulbar 13 (87) 41 (84) 0.78 54 (84)
Fornix 0 (0) 9 (18) 0.07 9 (14)
Tarsus 2 (13) 6 (12) 0.91 8 (13)
Plica semilunaris 0 (0) 1 (2) 0.99 1 (2)
Caruncle 0 (0) 2 (4) 0.99 2 (3)
Cornea 1 (7%) 40 (82) <0.001 41 (64)
Eyelid 0 (0) 2 (4) 0.99 2 (3)
Orbit 0 (0) 0 (0) NA 0 (0)
Quadrant involved
Superior 1 (7) 4 (8) 0.97 5 (8)
Temporal 3 (20) 10 (20) 13 (20)
Inferior 2 (13) 9 (18) 11 (17)
Nasal 9 (60) 25 (51) 34 (53)
Diffuse 0 (0) 1 (2) 1 (2)
Tumor Size
Largest basal diameter (mm) Mean (median, range) 5.5 (5.0, 1.0-12.0) 12.4 (10.0, 1.5-60.0) 0.001 10.8 (8.2, 1.0-60.0)
Number of clock hours involved Mean (median, range) 1.9 (2.0, 1.0-5.0) 4.1 (3.0, 1.0-12.0) 0.002 3.6 (3.0, 1.0-12.0)
Tumor Color
Pink 2 (13) 6 (12) 0.99 8 (12)
Yellow 10 (67) 34 (69) 44 (69)
White 3 (20) 9 (18) 12 (19)
Tumor Vascularity
Intrinsic vessels 8 (53) 28 (57) 0.80 36 (56)
Feeder vessels 6 (40) 18 (37) 0.82 24 (37)
Additional features
Leukoplakia 5 (33) 8 (16) 0.15 13 (20)
Internal cysts 1 (7) 0 (0) 0.23 1 (2)
Internal pigment 0 (0) 0 (0) NA 0 (0)
Bold values indicate significant P
Topical IFNα2b at a dose of 1 million IU/mL administered 4 times daily was used as primary monotherapy for all patients. The tumor response is listed in Table 3. There was no difference in percentage of patients lost to follow-up (7% vs. 2%, P = 0.42) or mean follow-up time (22.2 vs. 23.1 months, P = 0.87). A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with longer mean duration of IFNα2b monotherapy for tumor control (3.7 vs. 6.3 months, P = 0.002). There was no difference in complete tumor response (93% vs. 96%, (P = 0.65), partial response (7% vs. 2%), or no response (0% vs. 2%) (P = 0.54) [Fig. 1]. The single patient with no response had prior corneal graft and received topical IFNα2b with no improvement, and later required subconjunctival IFNα2b injection. There was no difference regarding mean time to complete response (5.0 vs. 6.1 months, P = 0.25). Following initial response, there was no difference in tumor recurrence (7% vs. 2%, P = 0.41). Regarding local treatment side effects, flat tumors had more frequent follicular reaction (20% vs. 2%, P = 0.04). There was no difference in ocular surface irritation or corneal epithelial defect. There were no patients who developed metastatic disease or death.
Table 3 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Outcomes
Outcomes Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
No follow-up 1 (7) 1 (2) 0.42 2 (3)
Tumor response n=14 n=48 n=62
Complete 13 (93) 46 (96) 0.54 59 (95)
Partial 1 (7)* 1 (2)** 2 (3)
No response 0 (0) 1 (2)*** 1 (2)
n=14 n=47 n=61
Recurrence after initial response 1 (7) 1 (2) 0.41 2 (3)
Additional treatment needed for complete response 1 (7) 6 (13) 0.68 7 (11)
Topical mitomycin C 0 (0) 1 (2) 0.99 1 (2)
Surgical excision 1 (7) 5 (9) 0.99 6 (10)
Local treatment side effects
Follicular reaction 3 (20) 1 (2) 0.04 4 (6)
Irritation 0 (0) 1 (2) 0.99 1 (2)
Corneal epithelial defect 0 (0) 1 (2) 0.99 2 (3)
Systemic outcomes
Metastasis 0 (0) 0 (0) NA 0 (0)
Death 0 (0) 0 (0) NA 0 (0)
Total duration of interferon alpha-2b therapy (months)
Mean (median, range) 3.7 (3.0, 0.5-7.0) 6.3 (6.0, 1.0-13.0) 0.002 5.7 (5.0, 0.5-13.0)
Time to complete response (months)
Mean (median, range) 5.0 (3.8, 1.0-11.5) 6.1 (5.4, 1.3-17.8) 0.25 5.8 (5.0, 1.0-17.8)
Follow-up time (months) n=14 n=48 n=62
Mean (median, range) 22.2 (14.3, 2.9-63.1) 23.1 (13.9, 1.3-114.6) 0.87 23.0 (14.4, 1.3-114.6)
Bold values indicate significant P. * Patient lost to follow-up after 7 months of therapy due to liver transplant. ** Patient stopped interferon alpha-2b after 1 month due to ocular surface discomfort and was lost to follow-up. *** Patient elected not to continue treatment after secondary treatment was advised
Figure 1 Treatment of ocular surface squamous neoplasia (OSSN) using topical interferon alpha-2b (IFNa2b) monotherapy. Flat vascular OSSN in a 76-year-old female (a) before and (b) after 4 months of IFNa2b monotherapy. Dome-shaped OSSN in a 57-year-old female (c) before and (d) after 8 months of IFNa2b monotherapy
Discussion
A recent report of 5002 conjunctival tumors from an ocular oncology center revealed that premalignant/malignant squamous neoplasia (OSSN) represented 729 (15%) of all cases, mostly with diagnoses of conjunctival intraepithelial neoplasia (CIN) (n = 275 tumors) or squamous cell carcinoma (SCC) (n = 440 tumors).[7] In that analysis, CIN or SCC was most often noted at the corneoscleral limbus (575/715, 80%), located nasally (269/715, 38%) or temporally (285/715, 40%), and appearing as a lump/swelling to the patient (434/715, 61%).
In 2012, Shah et al. reported the results of topical v for OSSN in 23 cases based on the 7th edition AJCC classification and noted that complete control was achieved in 83% of cases, specifically 67% of those labeled as Tis and 85% of the T3 group.[8] In that analysis there were no patients with T1, T2, or T4, as found in our current study. Further investigation of topical or injection IFNα2b for OSSN revealed applications for immunoreduction of giant OSSN, and immunoprevention in immunosuppressed patients, especially those with human immunodeficiency virus (HIV) or organ transplant who are at risk to have numerous and multifocal OSSN.[910] Galor et al. compared the topical dose of 1 million IU/ml to 3 million IU/mL IFNα2b and found no difference in tumor response, treatment duration, recurrence, or adverse effects.[11]
Since the above publications, the AJCC has been updated to the 8th edition. However, classification requires tumor biopsy and histopathologic analysis, but in this current era of topical therapies, clinicians often avoid biopsy when starting topical therapies if the diagnosis is clinical evident. Thus, AJCC classification is not possible for clinicians using purely topical therapies. In this report, we accommodate AJCC 8th edition classification by inferring that flat tumor configuration with no corneal component might serve as a surrogate for Tis and dome-shaped as T1, T2, T3, or T4.
In this analysis, we were able to provide a comparative analysis of tumor control with topical IFNα2b monotherapy without the need for biopsy. We found important differences in clinical features in that dome-shaped tumors occurred in older mean patient age (62 vs. 70 years, P = 0.04), with greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (0% vs. 84%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean clock hour extent (1.9 vs. 4.3, P = 0.002). To achieve control with topical IFNα2b, dome-shaped tumors tumors required greater mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002) for equivalent complete tumor control (93% vs. 96%, P = 0.65).
There are limitations to this study that should be considered. The data was a retrospective collection with inherent biases and drawbacks. Additionally, the cohort size was relatively small at 64 cases, resulting in limited statistical power, but due to the rarity of this malignancy and strict inclusion criteria of primary treatment with topical IFNα2b monotherapy only, our data represents pure data with few conflicting events. We recognize that precise AJCC classification could not be performed without histopathologic anaylsis, and microscopic invasion of the basement membrane in the case of flat tumor could have been missed. Nevertheless, with excellent tumor control for both flat and dome-shaped tumor, biopsy would not likely have changed our main study conclusion. Perhaps further studies could evaluate outcomes based on clinical imaging such as anterior segment optical coherence tomography or ultrasound biomicroscopy. Lastly, further follow-up with larger cohort in the future could potentially verify our observations.
Most previous studies on this topic have included pretreatment biopsy for diagnostic and staging confirmation, but that interferes with the ability to promptly employ some topical therapies and adds a confounding factor of the amount of tumor surgically excised versus the remnant of tumor left for treatment with topical therapy. Hence, we chose to avoid biopsy as this is consistent with how most clinicians currently approach clinically-evident OSSN, especially when starting topical therapy. Thus our results reflect the impact of topical IFNα2b monotherapy for the entire OSSN without the need for biopsy.
Conclusion
In conclusion, based on tumor configuration of OSSN, overall tumor control is 95% and does not differ when comparing flat to dome-shaped tumors. In addition, dome-shaped tumors required longer duration of therapy and demonstrated no greater recurrence upon discontinuation of the medication. We conclude that topical IFNα2b monotherapy is highly effective for the treatment of conjunctival OSSN, whether or not the tumor is flat or dome-shaped.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | INTERFERON ALFA-2B | DrugsGivenReaction | CC BY-NC-SA | 33595473 | 19,031,058 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Primary treatment of ocular surface squamous neoplasia with topical interferon alpha-2b: Comparative analysis of outcomes based on original tumor configuration.
The aim of this study was to evaluate tumor control of OSSN with topical IFNα2b alone based on tumor configuration (flat versus (vs.) dome-shaped).
Retrospective, nonrandomized, interventional cohort study on 64 consecutive tumors in 63 patients with OSSN treated with topical IFNα2b. Topical IFNα2b (1 million international units/cc) was compounded and provided by the Thomas Jefferson University Hospital Pharmacy to be refrigerated and applied 4 times daily until biomicroscopic evidence of tumor resolution was observed.
The tumor configuration was flat (n = 15, 23%) or dome-shaped (n = 49, 77%). A comparison (flat vs. dome-shaped) revealed dome-shaped with older mean patient age at presentation (62 vs. 70 years, P = 0.04), greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (7% vs. 82%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean thickness (1.9 vs. 4.3, P = 0.002), and longer mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002). There was no difference in mean follow-up time (22.2 vs 23.1 months) or time to complete response (5.0 vs. 6.1 months). There was no difference in achievement of complete tumor control with IFNα2b alone (93% vs. 96%). There were no cases with metastasis or death.
Topical IFNα2b alone shows excellent overall tumor control of 95% with no difference in efficacy based on tumor configuration.
Ocular surface squamous neoplasia (OSSN) is an umbrella term referring to the spectrum of squamous epithelial malignancy that can occur on the ocular surface, from in situ mild dysplasia to invasive epithelial malignant tumors. Based on the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study of 566,401 individuals aged 50-71 years, the incidence of OSSN was 8.4 per million persons, and found to be greater incidence in males (10.3 per million) and age >60 years (10.0 per million).[1] The management of this malignancy involves surgical and non-surgical alternatives, using topical or injection chemotherapy or immunotherapy. Several publications have explored the role of topical interferon alpha 2-B (IFNα2b) for tumor management.[123] A matched comparative analysis (IFNα2b (topical and injections) versus (vs.) surgery) for OSSN therapy revealed no difference in the recurrence rate (3% vs. 5%)[4] and non-significant equivalent cost for the full course of the two alternatives ($2831 vs $3528 US dollars (Medicare allowable charges)).[5] Thus, topical and injection IFNα2b for OSSN remains an important therapeutic alternative to surgery for affected patients.
Herein, we specifically focus on the role of topical IFNα2b monotherapy in the management of OSSN. In this analysis, we explore tumor control with topical IFNα2b based on tumor configuration (flat versus (vs.) dome-shaped). Many clinicians using topical therapies apply the medications based on classic tumor features and without the need for tumor biopsy, to spare the patient surgical intervention. Thus, tumor grouping by the American Joint Committee on Cancer (AJCC) Classification is not possible, as histopathology evaluation of tumor depth (in situ vs. deeper) is not available. However, one might speculate that tumor configuration as flat could serve as a surrogate for Tis and configuration as dome-shaped could represent T1, T2, T3, or T4 based on tumor basal dimension and adjacent tissue involvement as proposed by the AJCC.[6] Herein, we explore outcomes of topical IFNα2b based on practical tumor configuration, whether the tumor is thin (flat) or thick (dome-shaped).
Methods
The medical records of all patients with clinically-evident OSSN diagnosed and managed on the Ocular Oncology Service at Wills Eye Hospital, Philadelphia USA, between October 4, 2005, and January 28, 2019 were retrospectively reviewed. Patients were included if primary treatment for OSSN consisted only of topical IFNα2b monotherapy. Patients who received treatment prior to referral, or those who received subconjunctival injection of IFNα2b or were treated with prophylactic IFNα2b were excluded. The treatment protocol included use of IFNα2b (Intron-A, Schering-Plough, London UK) in a topical formulation of 1 million international units (IU)/mL compounded by Thomas Jefferson University Hospital Pharmacy, Philadelphia USA, and stored in refrigeration, avoiding disturbance or shaking of the bottle. The eye drops were administered 4 times daily until 1 month beyond clinical evidence of complete tumor resolution or until the time a secondary treatment was deemed necessary due to poor response. The response to treatment was monitored every 3 to 6 months and the duration of treatment was modified on the basis of tumor response. This study was approved by the Institutional Review Board of Wills Eye Hospital, Philadelphia USA and adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all patients.
All patients were examined by a trained ocular oncologist (CLS, SEL) with slit-lamp biomicroscopy, documentation on detailed, large conjunctival drawings, and with photographic documentation. The demographic data included age, race, sex, and Fitzpatrick skin type. Past medical history included risk factors of smoking status, autoimmune condition, chronic use (>6 months) of topical or systemic corticosteroids or other immunosuppressive medications, organ transplant, corneal graft, human papillomavirus (HPV) infection, human immunodeficiency virus infection, and cutaneous or mucous membrane squamous cell carcinoma. Clinical findings at presentation included best-corrected visual acuity), tumor laterality, tumor multiplicity, tissues involved (bulbar conjunctiva, forniceal conjunctiva, tarsal conjunctiva, plica semilunaris, caruncle, cornea, eyelid, and orbit), quadrant or location involved (superior, temporal, inferior, nasal, diffuse), largest tumor basal diameter, number of clock hours involved, tumor configuraton (flat, dome-shaped), lesion color, feeder and intrinsic vessels, leukoplakia, and internal pigment. The tumor configuration was considered flat if there was a flat surface of ≤1 mm thickness, whereas the tumors were considered dome-shaped if the mass gradually increased in thickness from the margin to a central apex and were >1 mm thickness centrally.
The number of months of topical IFNα2b therapy were recorded. At each follow-up examination, features were recorded regarding best-corrected visual acuity, tumor basal diameter, tissue involvement, and interferon-induced toxicity. Treatment outcomes included tumor control (complete, partial, or no response), recurrence, treatment for recurrence, metastasis, and death. Complete response was defined as complete tumor regression with total disappearance of tumor. Partial response was defined as tumor regression of less than 100%. No response was defined as no visible change following therapy. Recurrence was defined as reappearance of tumor at the primary tumor location after complete resolution following topical IFNα2b. Additional treatment required for tumor control after primary topical IFNα2b was noted. Spread to regional lymph nodes was assessed by history and palpation of preauricular, submental, submandibular, and cervical lymph nodes at each visit. Distant metastasis and death per the general medical physician were recorded.
Demographics, clinical features, and outcomes were compared by tumor configuration (flat vs. dome-shaped) using Fisher's exact test, Chi-squared test, and Mann Whitney U test. A P value <0.05 was considered significant.
Results
Of the 236 consecutive patients with clinically evident OSSN evaluated and managed on the Ocular Oncology Service, Wills Eye Hospital, during this time period, there were 64 tumors in 63 eyes of 63 patients that met inclusion criteria for this study. Tumors were classified according to surface configuration (flat (thin) (n = 15, 23%) vs. dome-shaped (thick) (n = 49, 77%)).
The patient demographic features are listed in Table 1. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with older mean patient age (62 vs. 70 years, P = 0.04) and greater frequency of smoking (13% vs. 42%, P = 0.04). There was no difference regarding patient race, sex, or Fitzpatrick Skin Type, autoimmune disease, immunosuppression, medical history of squamous neoplasia elsewhere, and tumor laterality and multiplicity.
Table 1 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases of 63 Patients. Demographic features
Demographic Features Flat [Tis] (n=15 patients) [n (%)] Dome-shaped [T3] (n=48 patients) [n (%)] P Total (n=63 patients) [n (%)]
Age (years)
Mean (median, range) 62 (61, 45-85) 70 (68, 30-97) 0.04 68 (64, 30-97)
Race
Caucasian 14 (93) 45 (94) 0.67 59 (94)
African American 1 (7) 1 (2) 2 (3)
Hispanic 0 (0) 1 (2) 1 (2)
Asian 0 (0) 1 (2) 1 (2)
Sex
Male 8 (53) 27 (56) 0.84 35 (56)
Female 7 (47) 21 (44) 28 (44)
Fitzpatrick Skin Type
I 4 (27) 17 (35) 0.73 21 (33)
II 9 (60) 23 (48) 32 (51)
III 1 (7) 5 (10) 6 (10)
IV 0 (0) 2 (4) 2 (3)
V 0 (0) 0 (0) 0 (0)
VI 1 (7) 1 (2) 2 (3)
Smoking History
Yes 2 (13) 20 (42) 0.04 22 (34)
No 13 (87) 28 (58) 42 (66)
Medical History - Autoimmune
Celiac 0 (0) 1 (2) 0.77 1 (2)
Ocular cicatricial pemphigoid 0 (0) 1 (2) 0.77 1 (2)
Psoriatic arthritis 1 (7) 0 (0) 0.23 1 (2)
Rheumatoid arthritis* 0 (0) 1 (2) 0.77 1 (2)
Sjögren’s syndrome* 0 (0) 1 (2) 0.77 1 (2)
Thyroiditis 0 (0) 1 (2) 0.77 1 (2)
Medical History - Immunosuppression
Chronic systemic corticosteroids 1 (7) 2 (4) 0.56 3 (5)
Chronic systemic immunosuppressants 1 (7) 2 (4) 0.56 3 (5)
Chronic topical corticosteroids 0 (0) 1 (2) 0.99 1 (2)
Organ transplant 0 (0) 1 (2) 0.99 1 (2)
Corneal graft 0 (0) 2 (4) 0.99 2 (3)
HPV history 1 (7) 1 (2) 0.42 2 (3)
Medical History - SCC History
Skin SCC 2 (13) 6 (13) 0.93 8 (13)
Mucosal SCC** 0 (0) 2 (4) 0.99 2 (3)
Laterality
Right 4 (27) 25 (52) 0.40 29 (46)
Left 11 (73) 23 (48) 34 (54)
Multiplicity of tumors
Single 15 (100) 47 (98) 0.99 62 (98)
Multiple 0 (0) 1 (2) 1 (2)
HPV=Human papilloma virus, SCC=squamous cell carcinoma. Bold values indicate significant P. * There was one patient diagnosed with both rheumatoid arthritis and Sjögren’s syndrome. **There was one case of oropharyngeal SCC and one case of rectal SCC
The tumor features are listed in Table 2. At presentation, there was no evidence of lymph node or distant metastatic disease. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with greater corneal involvement (7%% vs. 82%, P < 0.001), greater mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and greater mean clock hour involvement (1.9 vs. 4.1, P = 0.002). There was no difference in tumor quadrant, growth pattern, color, vascularity, or additional features.
Table 2 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Tumor characteristics
Tumor Characteristics Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
Tissue involved
Bulbar 13 (87) 41 (84) 0.78 54 (84)
Fornix 0 (0) 9 (18) 0.07 9 (14)
Tarsus 2 (13) 6 (12) 0.91 8 (13)
Plica semilunaris 0 (0) 1 (2) 0.99 1 (2)
Caruncle 0 (0) 2 (4) 0.99 2 (3)
Cornea 1 (7%) 40 (82) <0.001 41 (64)
Eyelid 0 (0) 2 (4) 0.99 2 (3)
Orbit 0 (0) 0 (0) NA 0 (0)
Quadrant involved
Superior 1 (7) 4 (8) 0.97 5 (8)
Temporal 3 (20) 10 (20) 13 (20)
Inferior 2 (13) 9 (18) 11 (17)
Nasal 9 (60) 25 (51) 34 (53)
Diffuse 0 (0) 1 (2) 1 (2)
Tumor Size
Largest basal diameter (mm) Mean (median, range) 5.5 (5.0, 1.0-12.0) 12.4 (10.0, 1.5-60.0) 0.001 10.8 (8.2, 1.0-60.0)
Number of clock hours involved Mean (median, range) 1.9 (2.0, 1.0-5.0) 4.1 (3.0, 1.0-12.0) 0.002 3.6 (3.0, 1.0-12.0)
Tumor Color
Pink 2 (13) 6 (12) 0.99 8 (12)
Yellow 10 (67) 34 (69) 44 (69)
White 3 (20) 9 (18) 12 (19)
Tumor Vascularity
Intrinsic vessels 8 (53) 28 (57) 0.80 36 (56)
Feeder vessels 6 (40) 18 (37) 0.82 24 (37)
Additional features
Leukoplakia 5 (33) 8 (16) 0.15 13 (20)
Internal cysts 1 (7) 0 (0) 0.23 1 (2)
Internal pigment 0 (0) 0 (0) NA 0 (0)
Bold values indicate significant P
Topical IFNα2b at a dose of 1 million IU/mL administered 4 times daily was used as primary monotherapy for all patients. The tumor response is listed in Table 3. There was no difference in percentage of patients lost to follow-up (7% vs. 2%, P = 0.42) or mean follow-up time (22.2 vs. 23.1 months, P = 0.87). A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with longer mean duration of IFNα2b monotherapy for tumor control (3.7 vs. 6.3 months, P = 0.002). There was no difference in complete tumor response (93% vs. 96%, (P = 0.65), partial response (7% vs. 2%), or no response (0% vs. 2%) (P = 0.54) [Fig. 1]. The single patient with no response had prior corneal graft and received topical IFNα2b with no improvement, and later required subconjunctival IFNα2b injection. There was no difference regarding mean time to complete response (5.0 vs. 6.1 months, P = 0.25). Following initial response, there was no difference in tumor recurrence (7% vs. 2%, P = 0.41). Regarding local treatment side effects, flat tumors had more frequent follicular reaction (20% vs. 2%, P = 0.04). There was no difference in ocular surface irritation or corneal epithelial defect. There were no patients who developed metastatic disease or death.
Table 3 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Outcomes
Outcomes Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
No follow-up 1 (7) 1 (2) 0.42 2 (3)
Tumor response n=14 n=48 n=62
Complete 13 (93) 46 (96) 0.54 59 (95)
Partial 1 (7)* 1 (2)** 2 (3)
No response 0 (0) 1 (2)*** 1 (2)
n=14 n=47 n=61
Recurrence after initial response 1 (7) 1 (2) 0.41 2 (3)
Additional treatment needed for complete response 1 (7) 6 (13) 0.68 7 (11)
Topical mitomycin C 0 (0) 1 (2) 0.99 1 (2)
Surgical excision 1 (7) 5 (9) 0.99 6 (10)
Local treatment side effects
Follicular reaction 3 (20) 1 (2) 0.04 4 (6)
Irritation 0 (0) 1 (2) 0.99 1 (2)
Corneal epithelial defect 0 (0) 1 (2) 0.99 2 (3)
Systemic outcomes
Metastasis 0 (0) 0 (0) NA 0 (0)
Death 0 (0) 0 (0) NA 0 (0)
Total duration of interferon alpha-2b therapy (months)
Mean (median, range) 3.7 (3.0, 0.5-7.0) 6.3 (6.0, 1.0-13.0) 0.002 5.7 (5.0, 0.5-13.0)
Time to complete response (months)
Mean (median, range) 5.0 (3.8, 1.0-11.5) 6.1 (5.4, 1.3-17.8) 0.25 5.8 (5.0, 1.0-17.8)
Follow-up time (months) n=14 n=48 n=62
Mean (median, range) 22.2 (14.3, 2.9-63.1) 23.1 (13.9, 1.3-114.6) 0.87 23.0 (14.4, 1.3-114.6)
Bold values indicate significant P. * Patient lost to follow-up after 7 months of therapy due to liver transplant. ** Patient stopped interferon alpha-2b after 1 month due to ocular surface discomfort and was lost to follow-up. *** Patient elected not to continue treatment after secondary treatment was advised
Figure 1 Treatment of ocular surface squamous neoplasia (OSSN) using topical interferon alpha-2b (IFNa2b) monotherapy. Flat vascular OSSN in a 76-year-old female (a) before and (b) after 4 months of IFNa2b monotherapy. Dome-shaped OSSN in a 57-year-old female (c) before and (d) after 8 months of IFNa2b monotherapy
Discussion
A recent report of 5002 conjunctival tumors from an ocular oncology center revealed that premalignant/malignant squamous neoplasia (OSSN) represented 729 (15%) of all cases, mostly with diagnoses of conjunctival intraepithelial neoplasia (CIN) (n = 275 tumors) or squamous cell carcinoma (SCC) (n = 440 tumors).[7] In that analysis, CIN or SCC was most often noted at the corneoscleral limbus (575/715, 80%), located nasally (269/715, 38%) or temporally (285/715, 40%), and appearing as a lump/swelling to the patient (434/715, 61%).
In 2012, Shah et al. reported the results of topical v for OSSN in 23 cases based on the 7th edition AJCC classification and noted that complete control was achieved in 83% of cases, specifically 67% of those labeled as Tis and 85% of the T3 group.[8] In that analysis there were no patients with T1, T2, or T4, as found in our current study. Further investigation of topical or injection IFNα2b for OSSN revealed applications for immunoreduction of giant OSSN, and immunoprevention in immunosuppressed patients, especially those with human immunodeficiency virus (HIV) or organ transplant who are at risk to have numerous and multifocal OSSN.[910] Galor et al. compared the topical dose of 1 million IU/ml to 3 million IU/mL IFNα2b and found no difference in tumor response, treatment duration, recurrence, or adverse effects.[11]
Since the above publications, the AJCC has been updated to the 8th edition. However, classification requires tumor biopsy and histopathologic analysis, but in this current era of topical therapies, clinicians often avoid biopsy when starting topical therapies if the diagnosis is clinical evident. Thus, AJCC classification is not possible for clinicians using purely topical therapies. In this report, we accommodate AJCC 8th edition classification by inferring that flat tumor configuration with no corneal component might serve as a surrogate for Tis and dome-shaped as T1, T2, T3, or T4.
In this analysis, we were able to provide a comparative analysis of tumor control with topical IFNα2b monotherapy without the need for biopsy. We found important differences in clinical features in that dome-shaped tumors occurred in older mean patient age (62 vs. 70 years, P = 0.04), with greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (0% vs. 84%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean clock hour extent (1.9 vs. 4.3, P = 0.002). To achieve control with topical IFNα2b, dome-shaped tumors tumors required greater mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002) for equivalent complete tumor control (93% vs. 96%, P = 0.65).
There are limitations to this study that should be considered. The data was a retrospective collection with inherent biases and drawbacks. Additionally, the cohort size was relatively small at 64 cases, resulting in limited statistical power, but due to the rarity of this malignancy and strict inclusion criteria of primary treatment with topical IFNα2b monotherapy only, our data represents pure data with few conflicting events. We recognize that precise AJCC classification could not be performed without histopathologic anaylsis, and microscopic invasion of the basement membrane in the case of flat tumor could have been missed. Nevertheless, with excellent tumor control for both flat and dome-shaped tumor, biopsy would not likely have changed our main study conclusion. Perhaps further studies could evaluate outcomes based on clinical imaging such as anterior segment optical coherence tomography or ultrasound biomicroscopy. Lastly, further follow-up with larger cohort in the future could potentially verify our observations.
Most previous studies on this topic have included pretreatment biopsy for diagnostic and staging confirmation, but that interferes with the ability to promptly employ some topical therapies and adds a confounding factor of the amount of tumor surgically excised versus the remnant of tumor left for treatment with topical therapy. Hence, we chose to avoid biopsy as this is consistent with how most clinicians currently approach clinically-evident OSSN, especially when starting topical therapy. Thus our results reflect the impact of topical IFNα2b monotherapy for the entire OSSN without the need for biopsy.
Conclusion
In conclusion, based on tumor configuration of OSSN, overall tumor control is 95% and does not differ when comparing flat to dome-shaped tumors. In addition, dome-shaped tumors required longer duration of therapy and demonstrated no greater recurrence upon discontinuation of the medication. We conclude that topical IFNα2b monotherapy is highly effective for the treatment of conjunctival OSSN, whether or not the tumor is flat or dome-shaped.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | INTERFERON ALFA-2B | DrugsGivenReaction | CC BY-NC-SA | 33595473 | 19,031,058 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product preparation issue'. | Primary treatment of ocular surface squamous neoplasia with topical interferon alpha-2b: Comparative analysis of outcomes based on original tumor configuration.
The aim of this study was to evaluate tumor control of OSSN with topical IFNα2b alone based on tumor configuration (flat versus (vs.) dome-shaped).
Retrospective, nonrandomized, interventional cohort study on 64 consecutive tumors in 63 patients with OSSN treated with topical IFNα2b. Topical IFNα2b (1 million international units/cc) was compounded and provided by the Thomas Jefferson University Hospital Pharmacy to be refrigerated and applied 4 times daily until biomicroscopic evidence of tumor resolution was observed.
The tumor configuration was flat (n = 15, 23%) or dome-shaped (n = 49, 77%). A comparison (flat vs. dome-shaped) revealed dome-shaped with older mean patient age at presentation (62 vs. 70 years, P = 0.04), greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (7% vs. 82%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean thickness (1.9 vs. 4.3, P = 0.002), and longer mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002). There was no difference in mean follow-up time (22.2 vs 23.1 months) or time to complete response (5.0 vs. 6.1 months). There was no difference in achievement of complete tumor control with IFNα2b alone (93% vs. 96%). There were no cases with metastasis or death.
Topical IFNα2b alone shows excellent overall tumor control of 95% with no difference in efficacy based on tumor configuration.
Ocular surface squamous neoplasia (OSSN) is an umbrella term referring to the spectrum of squamous epithelial malignancy that can occur on the ocular surface, from in situ mild dysplasia to invasive epithelial malignant tumors. Based on the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study of 566,401 individuals aged 50-71 years, the incidence of OSSN was 8.4 per million persons, and found to be greater incidence in males (10.3 per million) and age >60 years (10.0 per million).[1] The management of this malignancy involves surgical and non-surgical alternatives, using topical or injection chemotherapy or immunotherapy. Several publications have explored the role of topical interferon alpha 2-B (IFNα2b) for tumor management.[123] A matched comparative analysis (IFNα2b (topical and injections) versus (vs.) surgery) for OSSN therapy revealed no difference in the recurrence rate (3% vs. 5%)[4] and non-significant equivalent cost for the full course of the two alternatives ($2831 vs $3528 US dollars (Medicare allowable charges)).[5] Thus, topical and injection IFNα2b for OSSN remains an important therapeutic alternative to surgery for affected patients.
Herein, we specifically focus on the role of topical IFNα2b monotherapy in the management of OSSN. In this analysis, we explore tumor control with topical IFNα2b based on tumor configuration (flat versus (vs.) dome-shaped). Many clinicians using topical therapies apply the medications based on classic tumor features and without the need for tumor biopsy, to spare the patient surgical intervention. Thus, tumor grouping by the American Joint Committee on Cancer (AJCC) Classification is not possible, as histopathology evaluation of tumor depth (in situ vs. deeper) is not available. However, one might speculate that tumor configuration as flat could serve as a surrogate for Tis and configuration as dome-shaped could represent T1, T2, T3, or T4 based on tumor basal dimension and adjacent tissue involvement as proposed by the AJCC.[6] Herein, we explore outcomes of topical IFNα2b based on practical tumor configuration, whether the tumor is thin (flat) or thick (dome-shaped).
Methods
The medical records of all patients with clinically-evident OSSN diagnosed and managed on the Ocular Oncology Service at Wills Eye Hospital, Philadelphia USA, between October 4, 2005, and January 28, 2019 were retrospectively reviewed. Patients were included if primary treatment for OSSN consisted only of topical IFNα2b monotherapy. Patients who received treatment prior to referral, or those who received subconjunctival injection of IFNα2b or were treated with prophylactic IFNα2b were excluded. The treatment protocol included use of IFNα2b (Intron-A, Schering-Plough, London UK) in a topical formulation of 1 million international units (IU)/mL compounded by Thomas Jefferson University Hospital Pharmacy, Philadelphia USA, and stored in refrigeration, avoiding disturbance or shaking of the bottle. The eye drops were administered 4 times daily until 1 month beyond clinical evidence of complete tumor resolution or until the time a secondary treatment was deemed necessary due to poor response. The response to treatment was monitored every 3 to 6 months and the duration of treatment was modified on the basis of tumor response. This study was approved by the Institutional Review Board of Wills Eye Hospital, Philadelphia USA and adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all patients.
All patients were examined by a trained ocular oncologist (CLS, SEL) with slit-lamp biomicroscopy, documentation on detailed, large conjunctival drawings, and with photographic documentation. The demographic data included age, race, sex, and Fitzpatrick skin type. Past medical history included risk factors of smoking status, autoimmune condition, chronic use (>6 months) of topical or systemic corticosteroids or other immunosuppressive medications, organ transplant, corneal graft, human papillomavirus (HPV) infection, human immunodeficiency virus infection, and cutaneous or mucous membrane squamous cell carcinoma. Clinical findings at presentation included best-corrected visual acuity), tumor laterality, tumor multiplicity, tissues involved (bulbar conjunctiva, forniceal conjunctiva, tarsal conjunctiva, plica semilunaris, caruncle, cornea, eyelid, and orbit), quadrant or location involved (superior, temporal, inferior, nasal, diffuse), largest tumor basal diameter, number of clock hours involved, tumor configuraton (flat, dome-shaped), lesion color, feeder and intrinsic vessels, leukoplakia, and internal pigment. The tumor configuration was considered flat if there was a flat surface of ≤1 mm thickness, whereas the tumors were considered dome-shaped if the mass gradually increased in thickness from the margin to a central apex and were >1 mm thickness centrally.
The number of months of topical IFNα2b therapy were recorded. At each follow-up examination, features were recorded regarding best-corrected visual acuity, tumor basal diameter, tissue involvement, and interferon-induced toxicity. Treatment outcomes included tumor control (complete, partial, or no response), recurrence, treatment for recurrence, metastasis, and death. Complete response was defined as complete tumor regression with total disappearance of tumor. Partial response was defined as tumor regression of less than 100%. No response was defined as no visible change following therapy. Recurrence was defined as reappearance of tumor at the primary tumor location after complete resolution following topical IFNα2b. Additional treatment required for tumor control after primary topical IFNα2b was noted. Spread to regional lymph nodes was assessed by history and palpation of preauricular, submental, submandibular, and cervical lymph nodes at each visit. Distant metastasis and death per the general medical physician were recorded.
Demographics, clinical features, and outcomes were compared by tumor configuration (flat vs. dome-shaped) using Fisher's exact test, Chi-squared test, and Mann Whitney U test. A P value <0.05 was considered significant.
Results
Of the 236 consecutive patients with clinically evident OSSN evaluated and managed on the Ocular Oncology Service, Wills Eye Hospital, during this time period, there were 64 tumors in 63 eyes of 63 patients that met inclusion criteria for this study. Tumors were classified according to surface configuration (flat (thin) (n = 15, 23%) vs. dome-shaped (thick) (n = 49, 77%)).
The patient demographic features are listed in Table 1. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with older mean patient age (62 vs. 70 years, P = 0.04) and greater frequency of smoking (13% vs. 42%, P = 0.04). There was no difference regarding patient race, sex, or Fitzpatrick Skin Type, autoimmune disease, immunosuppression, medical history of squamous neoplasia elsewhere, and tumor laterality and multiplicity.
Table 1 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases of 63 Patients. Demographic features
Demographic Features Flat [Tis] (n=15 patients) [n (%)] Dome-shaped [T3] (n=48 patients) [n (%)] P Total (n=63 patients) [n (%)]
Age (years)
Mean (median, range) 62 (61, 45-85) 70 (68, 30-97) 0.04 68 (64, 30-97)
Race
Caucasian 14 (93) 45 (94) 0.67 59 (94)
African American 1 (7) 1 (2) 2 (3)
Hispanic 0 (0) 1 (2) 1 (2)
Asian 0 (0) 1 (2) 1 (2)
Sex
Male 8 (53) 27 (56) 0.84 35 (56)
Female 7 (47) 21 (44) 28 (44)
Fitzpatrick Skin Type
I 4 (27) 17 (35) 0.73 21 (33)
II 9 (60) 23 (48) 32 (51)
III 1 (7) 5 (10) 6 (10)
IV 0 (0) 2 (4) 2 (3)
V 0 (0) 0 (0) 0 (0)
VI 1 (7) 1 (2) 2 (3)
Smoking History
Yes 2 (13) 20 (42) 0.04 22 (34)
No 13 (87) 28 (58) 42 (66)
Medical History - Autoimmune
Celiac 0 (0) 1 (2) 0.77 1 (2)
Ocular cicatricial pemphigoid 0 (0) 1 (2) 0.77 1 (2)
Psoriatic arthritis 1 (7) 0 (0) 0.23 1 (2)
Rheumatoid arthritis* 0 (0) 1 (2) 0.77 1 (2)
Sjögren’s syndrome* 0 (0) 1 (2) 0.77 1 (2)
Thyroiditis 0 (0) 1 (2) 0.77 1 (2)
Medical History - Immunosuppression
Chronic systemic corticosteroids 1 (7) 2 (4) 0.56 3 (5)
Chronic systemic immunosuppressants 1 (7) 2 (4) 0.56 3 (5)
Chronic topical corticosteroids 0 (0) 1 (2) 0.99 1 (2)
Organ transplant 0 (0) 1 (2) 0.99 1 (2)
Corneal graft 0 (0) 2 (4) 0.99 2 (3)
HPV history 1 (7) 1 (2) 0.42 2 (3)
Medical History - SCC History
Skin SCC 2 (13) 6 (13) 0.93 8 (13)
Mucosal SCC** 0 (0) 2 (4) 0.99 2 (3)
Laterality
Right 4 (27) 25 (52) 0.40 29 (46)
Left 11 (73) 23 (48) 34 (54)
Multiplicity of tumors
Single 15 (100) 47 (98) 0.99 62 (98)
Multiple 0 (0) 1 (2) 1 (2)
HPV=Human papilloma virus, SCC=squamous cell carcinoma. Bold values indicate significant P. * There was one patient diagnosed with both rheumatoid arthritis and Sjögren’s syndrome. **There was one case of oropharyngeal SCC and one case of rectal SCC
The tumor features are listed in Table 2. At presentation, there was no evidence of lymph node or distant metastatic disease. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with greater corneal involvement (7%% vs. 82%, P < 0.001), greater mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and greater mean clock hour involvement (1.9 vs. 4.1, P = 0.002). There was no difference in tumor quadrant, growth pattern, color, vascularity, or additional features.
Table 2 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Tumor characteristics
Tumor Characteristics Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
Tissue involved
Bulbar 13 (87) 41 (84) 0.78 54 (84)
Fornix 0 (0) 9 (18) 0.07 9 (14)
Tarsus 2 (13) 6 (12) 0.91 8 (13)
Plica semilunaris 0 (0) 1 (2) 0.99 1 (2)
Caruncle 0 (0) 2 (4) 0.99 2 (3)
Cornea 1 (7%) 40 (82) <0.001 41 (64)
Eyelid 0 (0) 2 (4) 0.99 2 (3)
Orbit 0 (0) 0 (0) NA 0 (0)
Quadrant involved
Superior 1 (7) 4 (8) 0.97 5 (8)
Temporal 3 (20) 10 (20) 13 (20)
Inferior 2 (13) 9 (18) 11 (17)
Nasal 9 (60) 25 (51) 34 (53)
Diffuse 0 (0) 1 (2) 1 (2)
Tumor Size
Largest basal diameter (mm) Mean (median, range) 5.5 (5.0, 1.0-12.0) 12.4 (10.0, 1.5-60.0) 0.001 10.8 (8.2, 1.0-60.0)
Number of clock hours involved Mean (median, range) 1.9 (2.0, 1.0-5.0) 4.1 (3.0, 1.0-12.0) 0.002 3.6 (3.0, 1.0-12.0)
Tumor Color
Pink 2 (13) 6 (12) 0.99 8 (12)
Yellow 10 (67) 34 (69) 44 (69)
White 3 (20) 9 (18) 12 (19)
Tumor Vascularity
Intrinsic vessels 8 (53) 28 (57) 0.80 36 (56)
Feeder vessels 6 (40) 18 (37) 0.82 24 (37)
Additional features
Leukoplakia 5 (33) 8 (16) 0.15 13 (20)
Internal cysts 1 (7) 0 (0) 0.23 1 (2)
Internal pigment 0 (0) 0 (0) NA 0 (0)
Bold values indicate significant P
Topical IFNα2b at a dose of 1 million IU/mL administered 4 times daily was used as primary monotherapy for all patients. The tumor response is listed in Table 3. There was no difference in percentage of patients lost to follow-up (7% vs. 2%, P = 0.42) or mean follow-up time (22.2 vs. 23.1 months, P = 0.87). A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with longer mean duration of IFNα2b monotherapy for tumor control (3.7 vs. 6.3 months, P = 0.002). There was no difference in complete tumor response (93% vs. 96%, (P = 0.65), partial response (7% vs. 2%), or no response (0% vs. 2%) (P = 0.54) [Fig. 1]. The single patient with no response had prior corneal graft and received topical IFNα2b with no improvement, and later required subconjunctival IFNα2b injection. There was no difference regarding mean time to complete response (5.0 vs. 6.1 months, P = 0.25). Following initial response, there was no difference in tumor recurrence (7% vs. 2%, P = 0.41). Regarding local treatment side effects, flat tumors had more frequent follicular reaction (20% vs. 2%, P = 0.04). There was no difference in ocular surface irritation or corneal epithelial defect. There were no patients who developed metastatic disease or death.
Table 3 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Outcomes
Outcomes Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
No follow-up 1 (7) 1 (2) 0.42 2 (3)
Tumor response n=14 n=48 n=62
Complete 13 (93) 46 (96) 0.54 59 (95)
Partial 1 (7)* 1 (2)** 2 (3)
No response 0 (0) 1 (2)*** 1 (2)
n=14 n=47 n=61
Recurrence after initial response 1 (7) 1 (2) 0.41 2 (3)
Additional treatment needed for complete response 1 (7) 6 (13) 0.68 7 (11)
Topical mitomycin C 0 (0) 1 (2) 0.99 1 (2)
Surgical excision 1 (7) 5 (9) 0.99 6 (10)
Local treatment side effects
Follicular reaction 3 (20) 1 (2) 0.04 4 (6)
Irritation 0 (0) 1 (2) 0.99 1 (2)
Corneal epithelial defect 0 (0) 1 (2) 0.99 2 (3)
Systemic outcomes
Metastasis 0 (0) 0 (0) NA 0 (0)
Death 0 (0) 0 (0) NA 0 (0)
Total duration of interferon alpha-2b therapy (months)
Mean (median, range) 3.7 (3.0, 0.5-7.0) 6.3 (6.0, 1.0-13.0) 0.002 5.7 (5.0, 0.5-13.0)
Time to complete response (months)
Mean (median, range) 5.0 (3.8, 1.0-11.5) 6.1 (5.4, 1.3-17.8) 0.25 5.8 (5.0, 1.0-17.8)
Follow-up time (months) n=14 n=48 n=62
Mean (median, range) 22.2 (14.3, 2.9-63.1) 23.1 (13.9, 1.3-114.6) 0.87 23.0 (14.4, 1.3-114.6)
Bold values indicate significant P. * Patient lost to follow-up after 7 months of therapy due to liver transplant. ** Patient stopped interferon alpha-2b after 1 month due to ocular surface discomfort and was lost to follow-up. *** Patient elected not to continue treatment after secondary treatment was advised
Figure 1 Treatment of ocular surface squamous neoplasia (OSSN) using topical interferon alpha-2b (IFNa2b) monotherapy. Flat vascular OSSN in a 76-year-old female (a) before and (b) after 4 months of IFNa2b monotherapy. Dome-shaped OSSN in a 57-year-old female (c) before and (d) after 8 months of IFNa2b monotherapy
Discussion
A recent report of 5002 conjunctival tumors from an ocular oncology center revealed that premalignant/malignant squamous neoplasia (OSSN) represented 729 (15%) of all cases, mostly with diagnoses of conjunctival intraepithelial neoplasia (CIN) (n = 275 tumors) or squamous cell carcinoma (SCC) (n = 440 tumors).[7] In that analysis, CIN or SCC was most often noted at the corneoscleral limbus (575/715, 80%), located nasally (269/715, 38%) or temporally (285/715, 40%), and appearing as a lump/swelling to the patient (434/715, 61%).
In 2012, Shah et al. reported the results of topical v for OSSN in 23 cases based on the 7th edition AJCC classification and noted that complete control was achieved in 83% of cases, specifically 67% of those labeled as Tis and 85% of the T3 group.[8] In that analysis there were no patients with T1, T2, or T4, as found in our current study. Further investigation of topical or injection IFNα2b for OSSN revealed applications for immunoreduction of giant OSSN, and immunoprevention in immunosuppressed patients, especially those with human immunodeficiency virus (HIV) or organ transplant who are at risk to have numerous and multifocal OSSN.[910] Galor et al. compared the topical dose of 1 million IU/ml to 3 million IU/mL IFNα2b and found no difference in tumor response, treatment duration, recurrence, or adverse effects.[11]
Since the above publications, the AJCC has been updated to the 8th edition. However, classification requires tumor biopsy and histopathologic analysis, but in this current era of topical therapies, clinicians often avoid biopsy when starting topical therapies if the diagnosis is clinical evident. Thus, AJCC classification is not possible for clinicians using purely topical therapies. In this report, we accommodate AJCC 8th edition classification by inferring that flat tumor configuration with no corneal component might serve as a surrogate for Tis and dome-shaped as T1, T2, T3, or T4.
In this analysis, we were able to provide a comparative analysis of tumor control with topical IFNα2b monotherapy without the need for biopsy. We found important differences in clinical features in that dome-shaped tumors occurred in older mean patient age (62 vs. 70 years, P = 0.04), with greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (0% vs. 84%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean clock hour extent (1.9 vs. 4.3, P = 0.002). To achieve control with topical IFNα2b, dome-shaped tumors tumors required greater mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002) for equivalent complete tumor control (93% vs. 96%, P = 0.65).
There are limitations to this study that should be considered. The data was a retrospective collection with inherent biases and drawbacks. Additionally, the cohort size was relatively small at 64 cases, resulting in limited statistical power, but due to the rarity of this malignancy and strict inclusion criteria of primary treatment with topical IFNα2b monotherapy only, our data represents pure data with few conflicting events. We recognize that precise AJCC classification could not be performed without histopathologic anaylsis, and microscopic invasion of the basement membrane in the case of flat tumor could have been missed. Nevertheless, with excellent tumor control for both flat and dome-shaped tumor, biopsy would not likely have changed our main study conclusion. Perhaps further studies could evaluate outcomes based on clinical imaging such as anterior segment optical coherence tomography or ultrasound biomicroscopy. Lastly, further follow-up with larger cohort in the future could potentially verify our observations.
Most previous studies on this topic have included pretreatment biopsy for diagnostic and staging confirmation, but that interferes with the ability to promptly employ some topical therapies and adds a confounding factor of the amount of tumor surgically excised versus the remnant of tumor left for treatment with topical therapy. Hence, we chose to avoid biopsy as this is consistent with how most clinicians currently approach clinically-evident OSSN, especially when starting topical therapy. Thus our results reflect the impact of topical IFNα2b monotherapy for the entire OSSN without the need for biopsy.
Conclusion
In conclusion, based on tumor configuration of OSSN, overall tumor control is 95% and does not differ when comparing flat to dome-shaped tumors. In addition, dome-shaped tumors required longer duration of therapy and demonstrated no greater recurrence upon discontinuation of the medication. We conclude that topical IFNα2b monotherapy is highly effective for the treatment of conjunctival OSSN, whether or not the tumor is flat or dome-shaped.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | INTERFERON ALFA-2B | DrugsGivenReaction | CC BY-NC-SA | 33595473 | 19,031,058 | 2021-03 |
What was the administration route of drug 'INTERFERON ALFA-2B'? | Primary treatment of ocular surface squamous neoplasia with topical interferon alpha-2b: Comparative analysis of outcomes based on original tumor configuration.
The aim of this study was to evaluate tumor control of OSSN with topical IFNα2b alone based on tumor configuration (flat versus (vs.) dome-shaped).
Retrospective, nonrandomized, interventional cohort study on 64 consecutive tumors in 63 patients with OSSN treated with topical IFNα2b. Topical IFNα2b (1 million international units/cc) was compounded and provided by the Thomas Jefferson University Hospital Pharmacy to be refrigerated and applied 4 times daily until biomicroscopic evidence of tumor resolution was observed.
The tumor configuration was flat (n = 15, 23%) or dome-shaped (n = 49, 77%). A comparison (flat vs. dome-shaped) revealed dome-shaped with older mean patient age at presentation (62 vs. 70 years, P = 0.04), greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (7% vs. 82%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean thickness (1.9 vs. 4.3, P = 0.002), and longer mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002). There was no difference in mean follow-up time (22.2 vs 23.1 months) or time to complete response (5.0 vs. 6.1 months). There was no difference in achievement of complete tumor control with IFNα2b alone (93% vs. 96%). There were no cases with metastasis or death.
Topical IFNα2b alone shows excellent overall tumor control of 95% with no difference in efficacy based on tumor configuration.
Ocular surface squamous neoplasia (OSSN) is an umbrella term referring to the spectrum of squamous epithelial malignancy that can occur on the ocular surface, from in situ mild dysplasia to invasive epithelial malignant tumors. Based on the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study of 566,401 individuals aged 50-71 years, the incidence of OSSN was 8.4 per million persons, and found to be greater incidence in males (10.3 per million) and age >60 years (10.0 per million).[1] The management of this malignancy involves surgical and non-surgical alternatives, using topical or injection chemotherapy or immunotherapy. Several publications have explored the role of topical interferon alpha 2-B (IFNα2b) for tumor management.[123] A matched comparative analysis (IFNα2b (topical and injections) versus (vs.) surgery) for OSSN therapy revealed no difference in the recurrence rate (3% vs. 5%)[4] and non-significant equivalent cost for the full course of the two alternatives ($2831 vs $3528 US dollars (Medicare allowable charges)).[5] Thus, topical and injection IFNα2b for OSSN remains an important therapeutic alternative to surgery for affected patients.
Herein, we specifically focus on the role of topical IFNα2b monotherapy in the management of OSSN. In this analysis, we explore tumor control with topical IFNα2b based on tumor configuration (flat versus (vs.) dome-shaped). Many clinicians using topical therapies apply the medications based on classic tumor features and without the need for tumor biopsy, to spare the patient surgical intervention. Thus, tumor grouping by the American Joint Committee on Cancer (AJCC) Classification is not possible, as histopathology evaluation of tumor depth (in situ vs. deeper) is not available. However, one might speculate that tumor configuration as flat could serve as a surrogate for Tis and configuration as dome-shaped could represent T1, T2, T3, or T4 based on tumor basal dimension and adjacent tissue involvement as proposed by the AJCC.[6] Herein, we explore outcomes of topical IFNα2b based on practical tumor configuration, whether the tumor is thin (flat) or thick (dome-shaped).
Methods
The medical records of all patients with clinically-evident OSSN diagnosed and managed on the Ocular Oncology Service at Wills Eye Hospital, Philadelphia USA, between October 4, 2005, and January 28, 2019 were retrospectively reviewed. Patients were included if primary treatment for OSSN consisted only of topical IFNα2b monotherapy. Patients who received treatment prior to referral, or those who received subconjunctival injection of IFNα2b or were treated with prophylactic IFNα2b were excluded. The treatment protocol included use of IFNα2b (Intron-A, Schering-Plough, London UK) in a topical formulation of 1 million international units (IU)/mL compounded by Thomas Jefferson University Hospital Pharmacy, Philadelphia USA, and stored in refrigeration, avoiding disturbance or shaking of the bottle. The eye drops were administered 4 times daily until 1 month beyond clinical evidence of complete tumor resolution or until the time a secondary treatment was deemed necessary due to poor response. The response to treatment was monitored every 3 to 6 months and the duration of treatment was modified on the basis of tumor response. This study was approved by the Institutional Review Board of Wills Eye Hospital, Philadelphia USA and adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all patients.
All patients were examined by a trained ocular oncologist (CLS, SEL) with slit-lamp biomicroscopy, documentation on detailed, large conjunctival drawings, and with photographic documentation. The demographic data included age, race, sex, and Fitzpatrick skin type. Past medical history included risk factors of smoking status, autoimmune condition, chronic use (>6 months) of topical or systemic corticosteroids or other immunosuppressive medications, organ transplant, corneal graft, human papillomavirus (HPV) infection, human immunodeficiency virus infection, and cutaneous or mucous membrane squamous cell carcinoma. Clinical findings at presentation included best-corrected visual acuity), tumor laterality, tumor multiplicity, tissues involved (bulbar conjunctiva, forniceal conjunctiva, tarsal conjunctiva, plica semilunaris, caruncle, cornea, eyelid, and orbit), quadrant or location involved (superior, temporal, inferior, nasal, diffuse), largest tumor basal diameter, number of clock hours involved, tumor configuraton (flat, dome-shaped), lesion color, feeder and intrinsic vessels, leukoplakia, and internal pigment. The tumor configuration was considered flat if there was a flat surface of ≤1 mm thickness, whereas the tumors were considered dome-shaped if the mass gradually increased in thickness from the margin to a central apex and were >1 mm thickness centrally.
The number of months of topical IFNα2b therapy were recorded. At each follow-up examination, features were recorded regarding best-corrected visual acuity, tumor basal diameter, tissue involvement, and interferon-induced toxicity. Treatment outcomes included tumor control (complete, partial, or no response), recurrence, treatment for recurrence, metastasis, and death. Complete response was defined as complete tumor regression with total disappearance of tumor. Partial response was defined as tumor regression of less than 100%. No response was defined as no visible change following therapy. Recurrence was defined as reappearance of tumor at the primary tumor location after complete resolution following topical IFNα2b. Additional treatment required for tumor control after primary topical IFNα2b was noted. Spread to regional lymph nodes was assessed by history and palpation of preauricular, submental, submandibular, and cervical lymph nodes at each visit. Distant metastasis and death per the general medical physician were recorded.
Demographics, clinical features, and outcomes were compared by tumor configuration (flat vs. dome-shaped) using Fisher's exact test, Chi-squared test, and Mann Whitney U test. A P value <0.05 was considered significant.
Results
Of the 236 consecutive patients with clinically evident OSSN evaluated and managed on the Ocular Oncology Service, Wills Eye Hospital, during this time period, there were 64 tumors in 63 eyes of 63 patients that met inclusion criteria for this study. Tumors were classified according to surface configuration (flat (thin) (n = 15, 23%) vs. dome-shaped (thick) (n = 49, 77%)).
The patient demographic features are listed in Table 1. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with older mean patient age (62 vs. 70 years, P = 0.04) and greater frequency of smoking (13% vs. 42%, P = 0.04). There was no difference regarding patient race, sex, or Fitzpatrick Skin Type, autoimmune disease, immunosuppression, medical history of squamous neoplasia elsewhere, and tumor laterality and multiplicity.
Table 1 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases of 63 Patients. Demographic features
Demographic Features Flat [Tis] (n=15 patients) [n (%)] Dome-shaped [T3] (n=48 patients) [n (%)] P Total (n=63 patients) [n (%)]
Age (years)
Mean (median, range) 62 (61, 45-85) 70 (68, 30-97) 0.04 68 (64, 30-97)
Race
Caucasian 14 (93) 45 (94) 0.67 59 (94)
African American 1 (7) 1 (2) 2 (3)
Hispanic 0 (0) 1 (2) 1 (2)
Asian 0 (0) 1 (2) 1 (2)
Sex
Male 8 (53) 27 (56) 0.84 35 (56)
Female 7 (47) 21 (44) 28 (44)
Fitzpatrick Skin Type
I 4 (27) 17 (35) 0.73 21 (33)
II 9 (60) 23 (48) 32 (51)
III 1 (7) 5 (10) 6 (10)
IV 0 (0) 2 (4) 2 (3)
V 0 (0) 0 (0) 0 (0)
VI 1 (7) 1 (2) 2 (3)
Smoking History
Yes 2 (13) 20 (42) 0.04 22 (34)
No 13 (87) 28 (58) 42 (66)
Medical History - Autoimmune
Celiac 0 (0) 1 (2) 0.77 1 (2)
Ocular cicatricial pemphigoid 0 (0) 1 (2) 0.77 1 (2)
Psoriatic arthritis 1 (7) 0 (0) 0.23 1 (2)
Rheumatoid arthritis* 0 (0) 1 (2) 0.77 1 (2)
Sjögren’s syndrome* 0 (0) 1 (2) 0.77 1 (2)
Thyroiditis 0 (0) 1 (2) 0.77 1 (2)
Medical History - Immunosuppression
Chronic systemic corticosteroids 1 (7) 2 (4) 0.56 3 (5)
Chronic systemic immunosuppressants 1 (7) 2 (4) 0.56 3 (5)
Chronic topical corticosteroids 0 (0) 1 (2) 0.99 1 (2)
Organ transplant 0 (0) 1 (2) 0.99 1 (2)
Corneal graft 0 (0) 2 (4) 0.99 2 (3)
HPV history 1 (7) 1 (2) 0.42 2 (3)
Medical History - SCC History
Skin SCC 2 (13) 6 (13) 0.93 8 (13)
Mucosal SCC** 0 (0) 2 (4) 0.99 2 (3)
Laterality
Right 4 (27) 25 (52) 0.40 29 (46)
Left 11 (73) 23 (48) 34 (54)
Multiplicity of tumors
Single 15 (100) 47 (98) 0.99 62 (98)
Multiple 0 (0) 1 (2) 1 (2)
HPV=Human papilloma virus, SCC=squamous cell carcinoma. Bold values indicate significant P. * There was one patient diagnosed with both rheumatoid arthritis and Sjögren’s syndrome. **There was one case of oropharyngeal SCC and one case of rectal SCC
The tumor features are listed in Table 2. At presentation, there was no evidence of lymph node or distant metastatic disease. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with greater corneal involvement (7%% vs. 82%, P < 0.001), greater mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and greater mean clock hour involvement (1.9 vs. 4.1, P = 0.002). There was no difference in tumor quadrant, growth pattern, color, vascularity, or additional features.
Table 2 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Tumor characteristics
Tumor Characteristics Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
Tissue involved
Bulbar 13 (87) 41 (84) 0.78 54 (84)
Fornix 0 (0) 9 (18) 0.07 9 (14)
Tarsus 2 (13) 6 (12) 0.91 8 (13)
Plica semilunaris 0 (0) 1 (2) 0.99 1 (2)
Caruncle 0 (0) 2 (4) 0.99 2 (3)
Cornea 1 (7%) 40 (82) <0.001 41 (64)
Eyelid 0 (0) 2 (4) 0.99 2 (3)
Orbit 0 (0) 0 (0) NA 0 (0)
Quadrant involved
Superior 1 (7) 4 (8) 0.97 5 (8)
Temporal 3 (20) 10 (20) 13 (20)
Inferior 2 (13) 9 (18) 11 (17)
Nasal 9 (60) 25 (51) 34 (53)
Diffuse 0 (0) 1 (2) 1 (2)
Tumor Size
Largest basal diameter (mm) Mean (median, range) 5.5 (5.0, 1.0-12.0) 12.4 (10.0, 1.5-60.0) 0.001 10.8 (8.2, 1.0-60.0)
Number of clock hours involved Mean (median, range) 1.9 (2.0, 1.0-5.0) 4.1 (3.0, 1.0-12.0) 0.002 3.6 (3.0, 1.0-12.0)
Tumor Color
Pink 2 (13) 6 (12) 0.99 8 (12)
Yellow 10 (67) 34 (69) 44 (69)
White 3 (20) 9 (18) 12 (19)
Tumor Vascularity
Intrinsic vessels 8 (53) 28 (57) 0.80 36 (56)
Feeder vessels 6 (40) 18 (37) 0.82 24 (37)
Additional features
Leukoplakia 5 (33) 8 (16) 0.15 13 (20)
Internal cysts 1 (7) 0 (0) 0.23 1 (2)
Internal pigment 0 (0) 0 (0) NA 0 (0)
Bold values indicate significant P
Topical IFNα2b at a dose of 1 million IU/mL administered 4 times daily was used as primary monotherapy for all patients. The tumor response is listed in Table 3. There was no difference in percentage of patients lost to follow-up (7% vs. 2%, P = 0.42) or mean follow-up time (22.2 vs. 23.1 months, P = 0.87). A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with longer mean duration of IFNα2b monotherapy for tumor control (3.7 vs. 6.3 months, P = 0.002). There was no difference in complete tumor response (93% vs. 96%, (P = 0.65), partial response (7% vs. 2%), or no response (0% vs. 2%) (P = 0.54) [Fig. 1]. The single patient with no response had prior corneal graft and received topical IFNα2b with no improvement, and later required subconjunctival IFNα2b injection. There was no difference regarding mean time to complete response (5.0 vs. 6.1 months, P = 0.25). Following initial response, there was no difference in tumor recurrence (7% vs. 2%, P = 0.41). Regarding local treatment side effects, flat tumors had more frequent follicular reaction (20% vs. 2%, P = 0.04). There was no difference in ocular surface irritation or corneal epithelial defect. There were no patients who developed metastatic disease or death.
Table 3 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Outcomes
Outcomes Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
No follow-up 1 (7) 1 (2) 0.42 2 (3)
Tumor response n=14 n=48 n=62
Complete 13 (93) 46 (96) 0.54 59 (95)
Partial 1 (7)* 1 (2)** 2 (3)
No response 0 (0) 1 (2)*** 1 (2)
n=14 n=47 n=61
Recurrence after initial response 1 (7) 1 (2) 0.41 2 (3)
Additional treatment needed for complete response 1 (7) 6 (13) 0.68 7 (11)
Topical mitomycin C 0 (0) 1 (2) 0.99 1 (2)
Surgical excision 1 (7) 5 (9) 0.99 6 (10)
Local treatment side effects
Follicular reaction 3 (20) 1 (2) 0.04 4 (6)
Irritation 0 (0) 1 (2) 0.99 1 (2)
Corneal epithelial defect 0 (0) 1 (2) 0.99 2 (3)
Systemic outcomes
Metastasis 0 (0) 0 (0) NA 0 (0)
Death 0 (0) 0 (0) NA 0 (0)
Total duration of interferon alpha-2b therapy (months)
Mean (median, range) 3.7 (3.0, 0.5-7.0) 6.3 (6.0, 1.0-13.0) 0.002 5.7 (5.0, 0.5-13.0)
Time to complete response (months)
Mean (median, range) 5.0 (3.8, 1.0-11.5) 6.1 (5.4, 1.3-17.8) 0.25 5.8 (5.0, 1.0-17.8)
Follow-up time (months) n=14 n=48 n=62
Mean (median, range) 22.2 (14.3, 2.9-63.1) 23.1 (13.9, 1.3-114.6) 0.87 23.0 (14.4, 1.3-114.6)
Bold values indicate significant P. * Patient lost to follow-up after 7 months of therapy due to liver transplant. ** Patient stopped interferon alpha-2b after 1 month due to ocular surface discomfort and was lost to follow-up. *** Patient elected not to continue treatment after secondary treatment was advised
Figure 1 Treatment of ocular surface squamous neoplasia (OSSN) using topical interferon alpha-2b (IFNa2b) monotherapy. Flat vascular OSSN in a 76-year-old female (a) before and (b) after 4 months of IFNa2b monotherapy. Dome-shaped OSSN in a 57-year-old female (c) before and (d) after 8 months of IFNa2b monotherapy
Discussion
A recent report of 5002 conjunctival tumors from an ocular oncology center revealed that premalignant/malignant squamous neoplasia (OSSN) represented 729 (15%) of all cases, mostly with diagnoses of conjunctival intraepithelial neoplasia (CIN) (n = 275 tumors) or squamous cell carcinoma (SCC) (n = 440 tumors).[7] In that analysis, CIN or SCC was most often noted at the corneoscleral limbus (575/715, 80%), located nasally (269/715, 38%) or temporally (285/715, 40%), and appearing as a lump/swelling to the patient (434/715, 61%).
In 2012, Shah et al. reported the results of topical v for OSSN in 23 cases based on the 7th edition AJCC classification and noted that complete control was achieved in 83% of cases, specifically 67% of those labeled as Tis and 85% of the T3 group.[8] In that analysis there were no patients with T1, T2, or T4, as found in our current study. Further investigation of topical or injection IFNα2b for OSSN revealed applications for immunoreduction of giant OSSN, and immunoprevention in immunosuppressed patients, especially those with human immunodeficiency virus (HIV) or organ transplant who are at risk to have numerous and multifocal OSSN.[910] Galor et al. compared the topical dose of 1 million IU/ml to 3 million IU/mL IFNα2b and found no difference in tumor response, treatment duration, recurrence, or adverse effects.[11]
Since the above publications, the AJCC has been updated to the 8th edition. However, classification requires tumor biopsy and histopathologic analysis, but in this current era of topical therapies, clinicians often avoid biopsy when starting topical therapies if the diagnosis is clinical evident. Thus, AJCC classification is not possible for clinicians using purely topical therapies. In this report, we accommodate AJCC 8th edition classification by inferring that flat tumor configuration with no corneal component might serve as a surrogate for Tis and dome-shaped as T1, T2, T3, or T4.
In this analysis, we were able to provide a comparative analysis of tumor control with topical IFNα2b monotherapy without the need for biopsy. We found important differences in clinical features in that dome-shaped tumors occurred in older mean patient age (62 vs. 70 years, P = 0.04), with greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (0% vs. 84%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean clock hour extent (1.9 vs. 4.3, P = 0.002). To achieve control with topical IFNα2b, dome-shaped tumors tumors required greater mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002) for equivalent complete tumor control (93% vs. 96%, P = 0.65).
There are limitations to this study that should be considered. The data was a retrospective collection with inherent biases and drawbacks. Additionally, the cohort size was relatively small at 64 cases, resulting in limited statistical power, but due to the rarity of this malignancy and strict inclusion criteria of primary treatment with topical IFNα2b monotherapy only, our data represents pure data with few conflicting events. We recognize that precise AJCC classification could not be performed without histopathologic anaylsis, and microscopic invasion of the basement membrane in the case of flat tumor could have been missed. Nevertheless, with excellent tumor control for both flat and dome-shaped tumor, biopsy would not likely have changed our main study conclusion. Perhaps further studies could evaluate outcomes based on clinical imaging such as anterior segment optical coherence tomography or ultrasound biomicroscopy. Lastly, further follow-up with larger cohort in the future could potentially verify our observations.
Most previous studies on this topic have included pretreatment biopsy for diagnostic and staging confirmation, but that interferes with the ability to promptly employ some topical therapies and adds a confounding factor of the amount of tumor surgically excised versus the remnant of tumor left for treatment with topical therapy. Hence, we chose to avoid biopsy as this is consistent with how most clinicians currently approach clinically-evident OSSN, especially when starting topical therapy. Thus our results reflect the impact of topical IFNα2b monotherapy for the entire OSSN without the need for biopsy.
Conclusion
In conclusion, based on tumor configuration of OSSN, overall tumor control is 95% and does not differ when comparing flat to dome-shaped tumors. In addition, dome-shaped tumors required longer duration of therapy and demonstrated no greater recurrence upon discontinuation of the medication. We conclude that topical IFNα2b monotherapy is highly effective for the treatment of conjunctival OSSN, whether or not the tumor is flat or dome-shaped.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | Ophthalmic | DrugAdministrationRoute | CC BY-NC-SA | 33595473 | 19,031,058 | 2021-03 |
What was the dosage of drug 'INTERFERON ALFA-2B'? | Primary treatment of ocular surface squamous neoplasia with topical interferon alpha-2b: Comparative analysis of outcomes based on original tumor configuration.
The aim of this study was to evaluate tumor control of OSSN with topical IFNα2b alone based on tumor configuration (flat versus (vs.) dome-shaped).
Retrospective, nonrandomized, interventional cohort study on 64 consecutive tumors in 63 patients with OSSN treated with topical IFNα2b. Topical IFNα2b (1 million international units/cc) was compounded and provided by the Thomas Jefferson University Hospital Pharmacy to be refrigerated and applied 4 times daily until biomicroscopic evidence of tumor resolution was observed.
The tumor configuration was flat (n = 15, 23%) or dome-shaped (n = 49, 77%). A comparison (flat vs. dome-shaped) revealed dome-shaped with older mean patient age at presentation (62 vs. 70 years, P = 0.04), greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (7% vs. 82%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean thickness (1.9 vs. 4.3, P = 0.002), and longer mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002). There was no difference in mean follow-up time (22.2 vs 23.1 months) or time to complete response (5.0 vs. 6.1 months). There was no difference in achievement of complete tumor control with IFNα2b alone (93% vs. 96%). There were no cases with metastasis or death.
Topical IFNα2b alone shows excellent overall tumor control of 95% with no difference in efficacy based on tumor configuration.
Ocular surface squamous neoplasia (OSSN) is an umbrella term referring to the spectrum of squamous epithelial malignancy that can occur on the ocular surface, from in situ mild dysplasia to invasive epithelial malignant tumors. Based on the National Institutes of Health (NIH) American Association of Retired Persons (AARP) Diet and Health Study of 566,401 individuals aged 50-71 years, the incidence of OSSN was 8.4 per million persons, and found to be greater incidence in males (10.3 per million) and age >60 years (10.0 per million).[1] The management of this malignancy involves surgical and non-surgical alternatives, using topical or injection chemotherapy or immunotherapy. Several publications have explored the role of topical interferon alpha 2-B (IFNα2b) for tumor management.[123] A matched comparative analysis (IFNα2b (topical and injections) versus (vs.) surgery) for OSSN therapy revealed no difference in the recurrence rate (3% vs. 5%)[4] and non-significant equivalent cost for the full course of the two alternatives ($2831 vs $3528 US dollars (Medicare allowable charges)).[5] Thus, topical and injection IFNα2b for OSSN remains an important therapeutic alternative to surgery for affected patients.
Herein, we specifically focus on the role of topical IFNα2b monotherapy in the management of OSSN. In this analysis, we explore tumor control with topical IFNα2b based on tumor configuration (flat versus (vs.) dome-shaped). Many clinicians using topical therapies apply the medications based on classic tumor features and without the need for tumor biopsy, to spare the patient surgical intervention. Thus, tumor grouping by the American Joint Committee on Cancer (AJCC) Classification is not possible, as histopathology evaluation of tumor depth (in situ vs. deeper) is not available. However, one might speculate that tumor configuration as flat could serve as a surrogate for Tis and configuration as dome-shaped could represent T1, T2, T3, or T4 based on tumor basal dimension and adjacent tissue involvement as proposed by the AJCC.[6] Herein, we explore outcomes of topical IFNα2b based on practical tumor configuration, whether the tumor is thin (flat) or thick (dome-shaped).
Methods
The medical records of all patients with clinically-evident OSSN diagnosed and managed on the Ocular Oncology Service at Wills Eye Hospital, Philadelphia USA, between October 4, 2005, and January 28, 2019 were retrospectively reviewed. Patients were included if primary treatment for OSSN consisted only of topical IFNα2b monotherapy. Patients who received treatment prior to referral, or those who received subconjunctival injection of IFNα2b or were treated with prophylactic IFNα2b were excluded. The treatment protocol included use of IFNα2b (Intron-A, Schering-Plough, London UK) in a topical formulation of 1 million international units (IU)/mL compounded by Thomas Jefferson University Hospital Pharmacy, Philadelphia USA, and stored in refrigeration, avoiding disturbance or shaking of the bottle. The eye drops were administered 4 times daily until 1 month beyond clinical evidence of complete tumor resolution or until the time a secondary treatment was deemed necessary due to poor response. The response to treatment was monitored every 3 to 6 months and the duration of treatment was modified on the basis of tumor response. This study was approved by the Institutional Review Board of Wills Eye Hospital, Philadelphia USA and adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all patients.
All patients were examined by a trained ocular oncologist (CLS, SEL) with slit-lamp biomicroscopy, documentation on detailed, large conjunctival drawings, and with photographic documentation. The demographic data included age, race, sex, and Fitzpatrick skin type. Past medical history included risk factors of smoking status, autoimmune condition, chronic use (>6 months) of topical or systemic corticosteroids or other immunosuppressive medications, organ transplant, corneal graft, human papillomavirus (HPV) infection, human immunodeficiency virus infection, and cutaneous or mucous membrane squamous cell carcinoma. Clinical findings at presentation included best-corrected visual acuity), tumor laterality, tumor multiplicity, tissues involved (bulbar conjunctiva, forniceal conjunctiva, tarsal conjunctiva, plica semilunaris, caruncle, cornea, eyelid, and orbit), quadrant or location involved (superior, temporal, inferior, nasal, diffuse), largest tumor basal diameter, number of clock hours involved, tumor configuraton (flat, dome-shaped), lesion color, feeder and intrinsic vessels, leukoplakia, and internal pigment. The tumor configuration was considered flat if there was a flat surface of ≤1 mm thickness, whereas the tumors were considered dome-shaped if the mass gradually increased in thickness from the margin to a central apex and were >1 mm thickness centrally.
The number of months of topical IFNα2b therapy were recorded. At each follow-up examination, features were recorded regarding best-corrected visual acuity, tumor basal diameter, tissue involvement, and interferon-induced toxicity. Treatment outcomes included tumor control (complete, partial, or no response), recurrence, treatment for recurrence, metastasis, and death. Complete response was defined as complete tumor regression with total disappearance of tumor. Partial response was defined as tumor regression of less than 100%. No response was defined as no visible change following therapy. Recurrence was defined as reappearance of tumor at the primary tumor location after complete resolution following topical IFNα2b. Additional treatment required for tumor control after primary topical IFNα2b was noted. Spread to regional lymph nodes was assessed by history and palpation of preauricular, submental, submandibular, and cervical lymph nodes at each visit. Distant metastasis and death per the general medical physician were recorded.
Demographics, clinical features, and outcomes were compared by tumor configuration (flat vs. dome-shaped) using Fisher's exact test, Chi-squared test, and Mann Whitney U test. A P value <0.05 was considered significant.
Results
Of the 236 consecutive patients with clinically evident OSSN evaluated and managed on the Ocular Oncology Service, Wills Eye Hospital, during this time period, there were 64 tumors in 63 eyes of 63 patients that met inclusion criteria for this study. Tumors were classified according to surface configuration (flat (thin) (n = 15, 23%) vs. dome-shaped (thick) (n = 49, 77%)).
The patient demographic features are listed in Table 1. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with older mean patient age (62 vs. 70 years, P = 0.04) and greater frequency of smoking (13% vs. 42%, P = 0.04). There was no difference regarding patient race, sex, or Fitzpatrick Skin Type, autoimmune disease, immunosuppression, medical history of squamous neoplasia elsewhere, and tumor laterality and multiplicity.
Table 1 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases of 63 Patients. Demographic features
Demographic Features Flat [Tis] (n=15 patients) [n (%)] Dome-shaped [T3] (n=48 patients) [n (%)] P Total (n=63 patients) [n (%)]
Age (years)
Mean (median, range) 62 (61, 45-85) 70 (68, 30-97) 0.04 68 (64, 30-97)
Race
Caucasian 14 (93) 45 (94) 0.67 59 (94)
African American 1 (7) 1 (2) 2 (3)
Hispanic 0 (0) 1 (2) 1 (2)
Asian 0 (0) 1 (2) 1 (2)
Sex
Male 8 (53) 27 (56) 0.84 35 (56)
Female 7 (47) 21 (44) 28 (44)
Fitzpatrick Skin Type
I 4 (27) 17 (35) 0.73 21 (33)
II 9 (60) 23 (48) 32 (51)
III 1 (7) 5 (10) 6 (10)
IV 0 (0) 2 (4) 2 (3)
V 0 (0) 0 (0) 0 (0)
VI 1 (7) 1 (2) 2 (3)
Smoking History
Yes 2 (13) 20 (42) 0.04 22 (34)
No 13 (87) 28 (58) 42 (66)
Medical History - Autoimmune
Celiac 0 (0) 1 (2) 0.77 1 (2)
Ocular cicatricial pemphigoid 0 (0) 1 (2) 0.77 1 (2)
Psoriatic arthritis 1 (7) 0 (0) 0.23 1 (2)
Rheumatoid arthritis* 0 (0) 1 (2) 0.77 1 (2)
Sjögren’s syndrome* 0 (0) 1 (2) 0.77 1 (2)
Thyroiditis 0 (0) 1 (2) 0.77 1 (2)
Medical History - Immunosuppression
Chronic systemic corticosteroids 1 (7) 2 (4) 0.56 3 (5)
Chronic systemic immunosuppressants 1 (7) 2 (4) 0.56 3 (5)
Chronic topical corticosteroids 0 (0) 1 (2) 0.99 1 (2)
Organ transplant 0 (0) 1 (2) 0.99 1 (2)
Corneal graft 0 (0) 2 (4) 0.99 2 (3)
HPV history 1 (7) 1 (2) 0.42 2 (3)
Medical History - SCC History
Skin SCC 2 (13) 6 (13) 0.93 8 (13)
Mucosal SCC** 0 (0) 2 (4) 0.99 2 (3)
Laterality
Right 4 (27) 25 (52) 0.40 29 (46)
Left 11 (73) 23 (48) 34 (54)
Multiplicity of tumors
Single 15 (100) 47 (98) 0.99 62 (98)
Multiple 0 (0) 1 (2) 1 (2)
HPV=Human papilloma virus, SCC=squamous cell carcinoma. Bold values indicate significant P. * There was one patient diagnosed with both rheumatoid arthritis and Sjögren’s syndrome. **There was one case of oropharyngeal SCC and one case of rectal SCC
The tumor features are listed in Table 2. At presentation, there was no evidence of lymph node or distant metastatic disease. A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with greater corneal involvement (7%% vs. 82%, P < 0.001), greater mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and greater mean clock hour involvement (1.9 vs. 4.1, P = 0.002). There was no difference in tumor quadrant, growth pattern, color, vascularity, or additional features.
Table 2 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Tumor characteristics
Tumor Characteristics Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
Tissue involved
Bulbar 13 (87) 41 (84) 0.78 54 (84)
Fornix 0 (0) 9 (18) 0.07 9 (14)
Tarsus 2 (13) 6 (12) 0.91 8 (13)
Plica semilunaris 0 (0) 1 (2) 0.99 1 (2)
Caruncle 0 (0) 2 (4) 0.99 2 (3)
Cornea 1 (7%) 40 (82) <0.001 41 (64)
Eyelid 0 (0) 2 (4) 0.99 2 (3)
Orbit 0 (0) 0 (0) NA 0 (0)
Quadrant involved
Superior 1 (7) 4 (8) 0.97 5 (8)
Temporal 3 (20) 10 (20) 13 (20)
Inferior 2 (13) 9 (18) 11 (17)
Nasal 9 (60) 25 (51) 34 (53)
Diffuse 0 (0) 1 (2) 1 (2)
Tumor Size
Largest basal diameter (mm) Mean (median, range) 5.5 (5.0, 1.0-12.0) 12.4 (10.0, 1.5-60.0) 0.001 10.8 (8.2, 1.0-60.0)
Number of clock hours involved Mean (median, range) 1.9 (2.0, 1.0-5.0) 4.1 (3.0, 1.0-12.0) 0.002 3.6 (3.0, 1.0-12.0)
Tumor Color
Pink 2 (13) 6 (12) 0.99 8 (12)
Yellow 10 (67) 34 (69) 44 (69)
White 3 (20) 9 (18) 12 (19)
Tumor Vascularity
Intrinsic vessels 8 (53) 28 (57) 0.80 36 (56)
Feeder vessels 6 (40) 18 (37) 0.82 24 (37)
Additional features
Leukoplakia 5 (33) 8 (16) 0.15 13 (20)
Internal cysts 1 (7) 0 (0) 0.23 1 (2)
Internal pigment 0 (0) 0 (0) NA 0 (0)
Bold values indicate significant P
Topical IFNα2b at a dose of 1 million IU/mL administered 4 times daily was used as primary monotherapy for all patients. The tumor response is listed in Table 3. There was no difference in percentage of patients lost to follow-up (7% vs. 2%, P = 0.42) or mean follow-up time (22.2 vs. 23.1 months, P = 0.87). A comparison (flat vs. dome-shaped) revealed dome-shaped tumors with longer mean duration of IFNα2b monotherapy for tumor control (3.7 vs. 6.3 months, P = 0.002). There was no difference in complete tumor response (93% vs. 96%, (P = 0.65), partial response (7% vs. 2%), or no response (0% vs. 2%) (P = 0.54) [Fig. 1]. The single patient with no response had prior corneal graft and received topical IFNα2b with no improvement, and later required subconjunctival IFNα2b injection. There was no difference regarding mean time to complete response (5.0 vs. 6.1 months, P = 0.25). Following initial response, there was no difference in tumor recurrence (7% vs. 2%, P = 0.41). Regarding local treatment side effects, flat tumors had more frequent follicular reaction (20% vs. 2%, P = 0.04). There was no difference in ocular surface irritation or corneal epithelial defect. There were no patients who developed metastatic disease or death.
Table 3 Primary Treatment of Ocular Surface Squamous Neoplasia with Topical Interferon Alpha-2b in 64 Cases: Outcomes
Outcomes Flat [Tis] (n=15 tumors) [n (%)] Dome-shaped [T3] (n=49 tumors) [n (%)] P Total (n=64 tumors) [n (%)]
No follow-up 1 (7) 1 (2) 0.42 2 (3)
Tumor response n=14 n=48 n=62
Complete 13 (93) 46 (96) 0.54 59 (95)
Partial 1 (7)* 1 (2)** 2 (3)
No response 0 (0) 1 (2)*** 1 (2)
n=14 n=47 n=61
Recurrence after initial response 1 (7) 1 (2) 0.41 2 (3)
Additional treatment needed for complete response 1 (7) 6 (13) 0.68 7 (11)
Topical mitomycin C 0 (0) 1 (2) 0.99 1 (2)
Surgical excision 1 (7) 5 (9) 0.99 6 (10)
Local treatment side effects
Follicular reaction 3 (20) 1 (2) 0.04 4 (6)
Irritation 0 (0) 1 (2) 0.99 1 (2)
Corneal epithelial defect 0 (0) 1 (2) 0.99 2 (3)
Systemic outcomes
Metastasis 0 (0) 0 (0) NA 0 (0)
Death 0 (0) 0 (0) NA 0 (0)
Total duration of interferon alpha-2b therapy (months)
Mean (median, range) 3.7 (3.0, 0.5-7.0) 6.3 (6.0, 1.0-13.0) 0.002 5.7 (5.0, 0.5-13.0)
Time to complete response (months)
Mean (median, range) 5.0 (3.8, 1.0-11.5) 6.1 (5.4, 1.3-17.8) 0.25 5.8 (5.0, 1.0-17.8)
Follow-up time (months) n=14 n=48 n=62
Mean (median, range) 22.2 (14.3, 2.9-63.1) 23.1 (13.9, 1.3-114.6) 0.87 23.0 (14.4, 1.3-114.6)
Bold values indicate significant P. * Patient lost to follow-up after 7 months of therapy due to liver transplant. ** Patient stopped interferon alpha-2b after 1 month due to ocular surface discomfort and was lost to follow-up. *** Patient elected not to continue treatment after secondary treatment was advised
Figure 1 Treatment of ocular surface squamous neoplasia (OSSN) using topical interferon alpha-2b (IFNa2b) monotherapy. Flat vascular OSSN in a 76-year-old female (a) before and (b) after 4 months of IFNa2b monotherapy. Dome-shaped OSSN in a 57-year-old female (c) before and (d) after 8 months of IFNa2b monotherapy
Discussion
A recent report of 5002 conjunctival tumors from an ocular oncology center revealed that premalignant/malignant squamous neoplasia (OSSN) represented 729 (15%) of all cases, mostly with diagnoses of conjunctival intraepithelial neoplasia (CIN) (n = 275 tumors) or squamous cell carcinoma (SCC) (n = 440 tumors).[7] In that analysis, CIN or SCC was most often noted at the corneoscleral limbus (575/715, 80%), located nasally (269/715, 38%) or temporally (285/715, 40%), and appearing as a lump/swelling to the patient (434/715, 61%).
In 2012, Shah et al. reported the results of topical v for OSSN in 23 cases based on the 7th edition AJCC classification and noted that complete control was achieved in 83% of cases, specifically 67% of those labeled as Tis and 85% of the T3 group.[8] In that analysis there were no patients with T1, T2, or T4, as found in our current study. Further investigation of topical or injection IFNα2b for OSSN revealed applications for immunoreduction of giant OSSN, and immunoprevention in immunosuppressed patients, especially those with human immunodeficiency virus (HIV) or organ transplant who are at risk to have numerous and multifocal OSSN.[910] Galor et al. compared the topical dose of 1 million IU/ml to 3 million IU/mL IFNα2b and found no difference in tumor response, treatment duration, recurrence, or adverse effects.[11]
Since the above publications, the AJCC has been updated to the 8th edition. However, classification requires tumor biopsy and histopathologic analysis, but in this current era of topical therapies, clinicians often avoid biopsy when starting topical therapies if the diagnosis is clinical evident. Thus, AJCC classification is not possible for clinicians using purely topical therapies. In this report, we accommodate AJCC 8th edition classification by inferring that flat tumor configuration with no corneal component might serve as a surrogate for Tis and dome-shaped as T1, T2, T3, or T4.
In this analysis, we were able to provide a comparative analysis of tumor control with topical IFNα2b monotherapy without the need for biopsy. We found important differences in clinical features in that dome-shaped tumors occurred in older mean patient age (62 vs. 70 years, P = 0.04), with greater patient history of smoking (13% vs. 42%, P = 0.04), greater corneal involvement (0% vs. 84%, P < 0.001), larger mean basal diameter (5.5 vs. 12.4 mm, P = 0.001) and mean clock hour extent (1.9 vs. 4.3, P = 0.002). To achieve control with topical IFNα2b, dome-shaped tumors tumors required greater mean duration IFNα2b therapy (3.7 vs. 6.3 months, P = 0.002) for equivalent complete tumor control (93% vs. 96%, P = 0.65).
There are limitations to this study that should be considered. The data was a retrospective collection with inherent biases and drawbacks. Additionally, the cohort size was relatively small at 64 cases, resulting in limited statistical power, but due to the rarity of this malignancy and strict inclusion criteria of primary treatment with topical IFNα2b monotherapy only, our data represents pure data with few conflicting events. We recognize that precise AJCC classification could not be performed without histopathologic anaylsis, and microscopic invasion of the basement membrane in the case of flat tumor could have been missed. Nevertheless, with excellent tumor control for both flat and dome-shaped tumor, biopsy would not likely have changed our main study conclusion. Perhaps further studies could evaluate outcomes based on clinical imaging such as anterior segment optical coherence tomography or ultrasound biomicroscopy. Lastly, further follow-up with larger cohort in the future could potentially verify our observations.
Most previous studies on this topic have included pretreatment biopsy for diagnostic and staging confirmation, but that interferes with the ability to promptly employ some topical therapies and adds a confounding factor of the amount of tumor surgically excised versus the remnant of tumor left for treatment with topical therapy. Hence, we chose to avoid biopsy as this is consistent with how most clinicians currently approach clinically-evident OSSN, especially when starting topical therapy. Thus our results reflect the impact of topical IFNα2b monotherapy for the entire OSSN without the need for biopsy.
Conclusion
In conclusion, based on tumor configuration of OSSN, overall tumor control is 95% and does not differ when comparing flat to dome-shaped tumors. In addition, dome-shaped tumors required longer duration of therapy and demonstrated no greater recurrence upon discontinuation of the medication. We conclude that topical IFNα2b monotherapy is highly effective for the treatment of conjunctival OSSN, whether or not the tumor is flat or dome-shaped.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | 1 MILLION INTERNATIONAL UNITS (IU)/ML APPLIED 4 TIMES DAILY; TOPICAL EYE DROPS | DrugDosageText | CC BY-NC-SA | 33595473 | 19,031,058 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Prostate cancer'. | Cutaneous Metastasis of Prostate Adenocarcinoma: A Rare Presentation of a Common Disease.
Prostate cancer is the most common cancer affecting men in the United States and the second greatest cause of cancer-related death. Metastases usually occur to bone followed by distant lymph nodes and then viscera. Cutaneous metastases are extremely rare. Their presence indicates advanced disease and a poor prognosis. As they are highly variable in appearance and may mimic a more benign process, biopsy is essential for identification. Serine proteases, particularly human tissue kallikreins, may play an important role in promoting metastasis and facilitate infiltration of the skin. Individual cancer genetics may predispose to more aggressive cancer and thus earlier and more distant metastases. In this article, we report our case of a 67-year-old man with a 4-year history of castrate-resistant prostate cancer with cutaneous metastases confirmed by histology. Despite multiple lines of systemic therapy, the patient suffered progressive disease with worsening performance status and was enrolled in hospice.
Introduction
Prostate cancer is the most common malignancy in men, with an incidence of 106.5 per 100 000 in the United States, and the second most common cause of cancer-related death among American men after lung cancer.1 Common sites of metastasis include bone (84%), lymph nodes (10.6%), liver (10.2%), lung, and pleura (9.1%); however, metastasis to the skin is quite rare (≤0.36%).2-4 Cutaneous metastases tend to occur in the lower abdomen, thighs, and scrotum, but metastasis to chest, back, and face, or as a Sister Mary Joseph nodule have been reported.3-9 When present, it is often late in the course of the disease and considered an ominous sign; patients usually die within a year of its appearance.3-5
Case Description
A 67-year-old man with metastatic castration-resistant prostate cancer presented for evaluation of worsening skin lesions on his lower abdomen and suprapubic area (Figure 1). The patient was initially diagnosed with prostate cancer (Gleason 4 + 5) metastatic to bone in an outside country in June 2016. Prostate-specific antigen (PSA) was 1310 ng/mL at diagnosis, BUN (blood urea nitrogen) was 96 mg/dL, and creatinine was 3.6 mg/dL; all other laboratory values were within normal limits. He was treated with goserelin injections every 3 months with good response for 2 years when his PSA started rising again. He refused systemic treatment at that time. In 2019, he underwent left orchiectomy for a localized seminoma.
Figure 1. Metastasis of prostatic adenocarcinoma presenting as a confluence of reddish nodulopapular skin lesions over the bilateral lower abdomen with extension to the inguinal area and left flank. Left nephrostomy tube is visible.
In June 2019, he received a final dose of goserelin and moved to the United States to be with family and continue treatment. In July 2019, he was admitted for urinary retention and was found to have an acute kidney injury due to obstructive uropathy. Computed tomography of the abdomen and pelvis revealed bilateral hydronephrosis, hydroureter, and concentric bladder wall thickening despite a lack of urinary distention, suggesting neoplastic infiltration and obstruction of the ureteral outlets. There was significant retroperitoneal lymphadenopathy that was biopsied confirming metastasis of the prostate cancer. He received bilateral nephrostomies and one injection of degarelix followed by maintenance leuprolide every 4 months. His PSA was 420 ng/mL at that time, but rose to 784 ng/mL over the ensuing 2 months. He also had recurrent urinary infections that delayed his systemic treatment. He was started on abiraterone with prednisone.
After 1 month of therapy, his PSA improved to 118 ng/mL but rose again 3 months later to 220 ng/mL when he presented with numerous grouped, flesh-colored, nodulopapular skin lesions on his left lower abdomen, mons pubis, and left flank. Biopsy of these lesions demonstrated poorly differentiated carcinoma with foamy cytoplasm and pyknotic nuclei, expressing PSA and prostate-specific acid phosphatase (PSAP), consistent with metastasis from a high-grade prostatic adenocarcinoma (Figure 2). His treatment was switched to docetaxel with prednisone. After 6 cycles of docetaxel, his skin lesions had regressed. His PSA initially improved but then sharply rose to 481 ng/mL in June 2020 and his chemotherapy was switched to cabazitaxel.
Figure 2. Histological slides obtained from a punch biopsy of a skin lesion demonstrating poorly differentiated carcinoma with sheets of malignant cells and focally microacinar formation on hematoxylin and eosin staining (a). Immunohistochemical staining was positive for AE1/3 (b), weakly positive for prostate-specific antigen (c), and strongly positive for prostate-specific acid phosphatase (d).
Despite 5 cycles of cabazitaxel, his PSA continued to rise to 600 mg/mL, and his cutaneous metastases reappeared. Computed tomography of the abdomen and pelvis demonstrated significant worsening of disease with increased size of liver and lymphatic metastases, along with numerous osteoblastic lesions in the vertebrae. Next-generation sequencing revealed Myc amplification, FGFR1 amplification, and BRCA2 inactivation. However, at that point he had been bed bound for 2 months with contractures, dependent activities of daily living, stage III chronic kidney disease, and recurrent pyelonephritis with extended spectrum β-lactamase positive organisms. He was referred and enrolled in hospice care.
Discussion
This case serves as an example of an unusual presentation of a relatively common disease. Cutaneous metastasis from genitourinary tract carcinomas are rare, most frequently arising from the kidney (66%), followed by the bladder (17%), prostate (12%), and testes (4%).3 Prostate cancer usually first metastasizes to local lymph nodes and bone (hematogenously through Batson’s plexus), followed by lung, liver, and adrenal glands.2,9 If prostate cancer metastases to the skin it is almost always late in its course.3-5 These metastases are usually localized to the abdominopelvic region per literature review, distributed to the inguinal region and penis (28%), abdomen (23%), head and neck (16%), chest (14%), extremities (10%), and back (9%).10
The gross appearance of cutaneous metastases from prostate cancer is highly variable. Skin lesions most often initially present as multiple rubbery nodules or plaques, less often as a single nodule, and uncommonly as edema or a nonspecific rash.10,11 These may be asymptomatic or painful and ulcerated.9,12 Their appearance may resemble zoster, basal cell carcinoma, angiosarcoma, cellulitis, pyoderma gangrenosum, mammary Paget’s disease, telangiectasia, morphea, sebaceous cysts, or trichoepitheliomas.11-13 Biopsy of these lesions is required for definitive diagnosis.
Histological examination of biopsy specimens typically demonstrates acinar adenocarcinoma, but rare variants including atrophic, ductal, xanthomatous, mucinous, signet cell, squamous, urothelial, small cell, or mixed subtypes are possible.14,15 PSA and PSAP are specific to benign or malignant epithelial cells of the prostate gland.15-17 NKX3.1 and prostein (P501s) are highly sensitive and specific, but may also be present in sex cord stromal tumors.17,18 GATA3, p63, 34βE12, thrombomodulin, and cytokeratins (CK) 7 and 20 are often positive in urothelial cancer and typically negative in adenocarcinoma of the prostate.11,15,16 Very poorly differentiated cancers may be exceptional to the aforementioned immunohistochemical staining patterns (eg, PSA negative).15,16 In our case, biopsy of the cutaneous lesions demonstrated strong reactivity for PSAP, minor reactivity for PSA, while both CK7 and CK20 were negative, confirming the nature of the lesions as being metastatic prostate adenocarcinoma.
The route of metastasis of prostate cancer to the skin is not precisely known but may occur through lymphatic or hematogenous spread from the primary tumor with extravasation and invasion of the dermis, direct extension from another site of metastasis, or seeding from a surgical instrument.9,19 Serine proteases such as human tissue kallikreins may play a role in the ability of prostate cancer to infiltrate the skin by breaking down cell-cell adhesions in the epidermis.20 Furthermore, they are involved in the epithelial-mesenchymal transition, a process by which epithelial cells lose their epithelial characteristics and take on those of mesenchymal tissue—a major step in the progression of cancer and a driving factor for metastasis.20
Cutaneous metastases may be treated locally or systemically. Electron radiation therapy has been employed as an effective palliative treatment for painful skin metastases.21,22 Surgical excision and intralesional chemotherapy are also viable options for small and limited metastases.9,10 Systemic chemotherapy has the advantage of potentially reducing the primary malignancy as well as visceral and osseous metastases. According to one review, systemic treatment of the primary malignancy results in at least partial improvement in 65% of cases of cutaneous metastases within 4 to 8 weeks of initiating treatment.9 Our patient’s skin metastases demonstrated a similar response, initially regressing with systemic docetaxel and prednisone and completely disappearing by the second dose. The lesions did not recur until 9 months later when the cancer had stopped responding to taxanes and overall progressed leading to a decline in performance status and enrollment in hospice.
Conclusion
While prostate cancer is the most common cancer affecting men in the United States, metastasis to the skin is very rare and usually indicates advanced disease and a poor prognosis. Factors enabling or promoting cutaneous metastasis may include the human tissue kallikrein family of serine proteases and individual cancer genetics. Localized palliative therapy may be employed for symptomatic cutaneous metastases in select patients; however, systemic therapy is usually preferred. Although initially responsive to androgen deprivation therapy, prostate cancer inevitably becomes castrate resistant. As next-generation sequencing technologies become more widely available personalized therapy targeting specific mutations in an individual cancer is likely to become more commonplace, which may improve outcomes in cases like ours.
Teaching Points
Cutaneous metastasis of urologic cancers, including those of the prostate, are rare and associated with advanced disease and a poor prognosis.
Expression of tissue kallikreins may enhance cancer cell mobilization and facilitate metastatic infiltration of the skin.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases.
Informed Consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
ORCID iD: Alexander Dills
https://orcid.org/0000-0002-8770-7935 | DEGARELIX, LEUPROLIDE ACETATE | DrugsGivenReaction | CC BY-NC | 33596692 | 19,062,739 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Urinary tract infection'. | Cutaneous Metastasis of Prostate Adenocarcinoma: A Rare Presentation of a Common Disease.
Prostate cancer is the most common cancer affecting men in the United States and the second greatest cause of cancer-related death. Metastases usually occur to bone followed by distant lymph nodes and then viscera. Cutaneous metastases are extremely rare. Their presence indicates advanced disease and a poor prognosis. As they are highly variable in appearance and may mimic a more benign process, biopsy is essential for identification. Serine proteases, particularly human tissue kallikreins, may play an important role in promoting metastasis and facilitate infiltration of the skin. Individual cancer genetics may predispose to more aggressive cancer and thus earlier and more distant metastases. In this article, we report our case of a 67-year-old man with a 4-year history of castrate-resistant prostate cancer with cutaneous metastases confirmed by histology. Despite multiple lines of systemic therapy, the patient suffered progressive disease with worsening performance status and was enrolled in hospice.
Introduction
Prostate cancer is the most common malignancy in men, with an incidence of 106.5 per 100 000 in the United States, and the second most common cause of cancer-related death among American men after lung cancer.1 Common sites of metastasis include bone (84%), lymph nodes (10.6%), liver (10.2%), lung, and pleura (9.1%); however, metastasis to the skin is quite rare (≤0.36%).2-4 Cutaneous metastases tend to occur in the lower abdomen, thighs, and scrotum, but metastasis to chest, back, and face, or as a Sister Mary Joseph nodule have been reported.3-9 When present, it is often late in the course of the disease and considered an ominous sign; patients usually die within a year of its appearance.3-5
Case Description
A 67-year-old man with metastatic castration-resistant prostate cancer presented for evaluation of worsening skin lesions on his lower abdomen and suprapubic area (Figure 1). The patient was initially diagnosed with prostate cancer (Gleason 4 + 5) metastatic to bone in an outside country in June 2016. Prostate-specific antigen (PSA) was 1310 ng/mL at diagnosis, BUN (blood urea nitrogen) was 96 mg/dL, and creatinine was 3.6 mg/dL; all other laboratory values were within normal limits. He was treated with goserelin injections every 3 months with good response for 2 years when his PSA started rising again. He refused systemic treatment at that time. In 2019, he underwent left orchiectomy for a localized seminoma.
Figure 1. Metastasis of prostatic adenocarcinoma presenting as a confluence of reddish nodulopapular skin lesions over the bilateral lower abdomen with extension to the inguinal area and left flank. Left nephrostomy tube is visible.
In June 2019, he received a final dose of goserelin and moved to the United States to be with family and continue treatment. In July 2019, he was admitted for urinary retention and was found to have an acute kidney injury due to obstructive uropathy. Computed tomography of the abdomen and pelvis revealed bilateral hydronephrosis, hydroureter, and concentric bladder wall thickening despite a lack of urinary distention, suggesting neoplastic infiltration and obstruction of the ureteral outlets. There was significant retroperitoneal lymphadenopathy that was biopsied confirming metastasis of the prostate cancer. He received bilateral nephrostomies and one injection of degarelix followed by maintenance leuprolide every 4 months. His PSA was 420 ng/mL at that time, but rose to 784 ng/mL over the ensuing 2 months. He also had recurrent urinary infections that delayed his systemic treatment. He was started on abiraterone with prednisone.
After 1 month of therapy, his PSA improved to 118 ng/mL but rose again 3 months later to 220 ng/mL when he presented with numerous grouped, flesh-colored, nodulopapular skin lesions on his left lower abdomen, mons pubis, and left flank. Biopsy of these lesions demonstrated poorly differentiated carcinoma with foamy cytoplasm and pyknotic nuclei, expressing PSA and prostate-specific acid phosphatase (PSAP), consistent with metastasis from a high-grade prostatic adenocarcinoma (Figure 2). His treatment was switched to docetaxel with prednisone. After 6 cycles of docetaxel, his skin lesions had regressed. His PSA initially improved but then sharply rose to 481 ng/mL in June 2020 and his chemotherapy was switched to cabazitaxel.
Figure 2. Histological slides obtained from a punch biopsy of a skin lesion demonstrating poorly differentiated carcinoma with sheets of malignant cells and focally microacinar formation on hematoxylin and eosin staining (a). Immunohistochemical staining was positive for AE1/3 (b), weakly positive for prostate-specific antigen (c), and strongly positive for prostate-specific acid phosphatase (d).
Despite 5 cycles of cabazitaxel, his PSA continued to rise to 600 mg/mL, and his cutaneous metastases reappeared. Computed tomography of the abdomen and pelvis demonstrated significant worsening of disease with increased size of liver and lymphatic metastases, along with numerous osteoblastic lesions in the vertebrae. Next-generation sequencing revealed Myc amplification, FGFR1 amplification, and BRCA2 inactivation. However, at that point he had been bed bound for 2 months with contractures, dependent activities of daily living, stage III chronic kidney disease, and recurrent pyelonephritis with extended spectrum β-lactamase positive organisms. He was referred and enrolled in hospice care.
Discussion
This case serves as an example of an unusual presentation of a relatively common disease. Cutaneous metastasis from genitourinary tract carcinomas are rare, most frequently arising from the kidney (66%), followed by the bladder (17%), prostate (12%), and testes (4%).3 Prostate cancer usually first metastasizes to local lymph nodes and bone (hematogenously through Batson’s plexus), followed by lung, liver, and adrenal glands.2,9 If prostate cancer metastases to the skin it is almost always late in its course.3-5 These metastases are usually localized to the abdominopelvic region per literature review, distributed to the inguinal region and penis (28%), abdomen (23%), head and neck (16%), chest (14%), extremities (10%), and back (9%).10
The gross appearance of cutaneous metastases from prostate cancer is highly variable. Skin lesions most often initially present as multiple rubbery nodules or plaques, less often as a single nodule, and uncommonly as edema or a nonspecific rash.10,11 These may be asymptomatic or painful and ulcerated.9,12 Their appearance may resemble zoster, basal cell carcinoma, angiosarcoma, cellulitis, pyoderma gangrenosum, mammary Paget’s disease, telangiectasia, morphea, sebaceous cysts, or trichoepitheliomas.11-13 Biopsy of these lesions is required for definitive diagnosis.
Histological examination of biopsy specimens typically demonstrates acinar adenocarcinoma, but rare variants including atrophic, ductal, xanthomatous, mucinous, signet cell, squamous, urothelial, small cell, or mixed subtypes are possible.14,15 PSA and PSAP are specific to benign or malignant epithelial cells of the prostate gland.15-17 NKX3.1 and prostein (P501s) are highly sensitive and specific, but may also be present in sex cord stromal tumors.17,18 GATA3, p63, 34βE12, thrombomodulin, and cytokeratins (CK) 7 and 20 are often positive in urothelial cancer and typically negative in adenocarcinoma of the prostate.11,15,16 Very poorly differentiated cancers may be exceptional to the aforementioned immunohistochemical staining patterns (eg, PSA negative).15,16 In our case, biopsy of the cutaneous lesions demonstrated strong reactivity for PSAP, minor reactivity for PSA, while both CK7 and CK20 were negative, confirming the nature of the lesions as being metastatic prostate adenocarcinoma.
The route of metastasis of prostate cancer to the skin is not precisely known but may occur through lymphatic or hematogenous spread from the primary tumor with extravasation and invasion of the dermis, direct extension from another site of metastasis, or seeding from a surgical instrument.9,19 Serine proteases such as human tissue kallikreins may play a role in the ability of prostate cancer to infiltrate the skin by breaking down cell-cell adhesions in the epidermis.20 Furthermore, they are involved in the epithelial-mesenchymal transition, a process by which epithelial cells lose their epithelial characteristics and take on those of mesenchymal tissue—a major step in the progression of cancer and a driving factor for metastasis.20
Cutaneous metastases may be treated locally or systemically. Electron radiation therapy has been employed as an effective palliative treatment for painful skin metastases.21,22 Surgical excision and intralesional chemotherapy are also viable options for small and limited metastases.9,10 Systemic chemotherapy has the advantage of potentially reducing the primary malignancy as well as visceral and osseous metastases. According to one review, systemic treatment of the primary malignancy results in at least partial improvement in 65% of cases of cutaneous metastases within 4 to 8 weeks of initiating treatment.9 Our patient’s skin metastases demonstrated a similar response, initially regressing with systemic docetaxel and prednisone and completely disappearing by the second dose. The lesions did not recur until 9 months later when the cancer had stopped responding to taxanes and overall progressed leading to a decline in performance status and enrollment in hospice.
Conclusion
While prostate cancer is the most common cancer affecting men in the United States, metastasis to the skin is very rare and usually indicates advanced disease and a poor prognosis. Factors enabling or promoting cutaneous metastasis may include the human tissue kallikrein family of serine proteases and individual cancer genetics. Localized palliative therapy may be employed for symptomatic cutaneous metastases in select patients; however, systemic therapy is usually preferred. Although initially responsive to androgen deprivation therapy, prostate cancer inevitably becomes castrate resistant. As next-generation sequencing technologies become more widely available personalized therapy targeting specific mutations in an individual cancer is likely to become more commonplace, which may improve outcomes in cases like ours.
Teaching Points
Cutaneous metastasis of urologic cancers, including those of the prostate, are rare and associated with advanced disease and a poor prognosis.
Expression of tissue kallikreins may enhance cancer cell mobilization and facilitate metastatic infiltration of the skin.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases.
Informed Consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
ORCID iD: Alexander Dills
https://orcid.org/0000-0002-8770-7935 | DEGARELIX, LEUPROLIDE ACETATE | DrugsGivenReaction | CC BY-NC | 33596692 | 19,062,739 | 2021 |
What was the dosage of drug 'DEGARELIX'? | Cutaneous Metastasis of Prostate Adenocarcinoma: A Rare Presentation of a Common Disease.
Prostate cancer is the most common cancer affecting men in the United States and the second greatest cause of cancer-related death. Metastases usually occur to bone followed by distant lymph nodes and then viscera. Cutaneous metastases are extremely rare. Their presence indicates advanced disease and a poor prognosis. As they are highly variable in appearance and may mimic a more benign process, biopsy is essential for identification. Serine proteases, particularly human tissue kallikreins, may play an important role in promoting metastasis and facilitate infiltration of the skin. Individual cancer genetics may predispose to more aggressive cancer and thus earlier and more distant metastases. In this article, we report our case of a 67-year-old man with a 4-year history of castrate-resistant prostate cancer with cutaneous metastases confirmed by histology. Despite multiple lines of systemic therapy, the patient suffered progressive disease with worsening performance status and was enrolled in hospice.
Introduction
Prostate cancer is the most common malignancy in men, with an incidence of 106.5 per 100 000 in the United States, and the second most common cause of cancer-related death among American men after lung cancer.1 Common sites of metastasis include bone (84%), lymph nodes (10.6%), liver (10.2%), lung, and pleura (9.1%); however, metastasis to the skin is quite rare (≤0.36%).2-4 Cutaneous metastases tend to occur in the lower abdomen, thighs, and scrotum, but metastasis to chest, back, and face, or as a Sister Mary Joseph nodule have been reported.3-9 When present, it is often late in the course of the disease and considered an ominous sign; patients usually die within a year of its appearance.3-5
Case Description
A 67-year-old man with metastatic castration-resistant prostate cancer presented for evaluation of worsening skin lesions on his lower abdomen and suprapubic area (Figure 1). The patient was initially diagnosed with prostate cancer (Gleason 4 + 5) metastatic to bone in an outside country in June 2016. Prostate-specific antigen (PSA) was 1310 ng/mL at diagnosis, BUN (blood urea nitrogen) was 96 mg/dL, and creatinine was 3.6 mg/dL; all other laboratory values were within normal limits. He was treated with goserelin injections every 3 months with good response for 2 years when his PSA started rising again. He refused systemic treatment at that time. In 2019, he underwent left orchiectomy for a localized seminoma.
Figure 1. Metastasis of prostatic adenocarcinoma presenting as a confluence of reddish nodulopapular skin lesions over the bilateral lower abdomen with extension to the inguinal area and left flank. Left nephrostomy tube is visible.
In June 2019, he received a final dose of goserelin and moved to the United States to be with family and continue treatment. In July 2019, he was admitted for urinary retention and was found to have an acute kidney injury due to obstructive uropathy. Computed tomography of the abdomen and pelvis revealed bilateral hydronephrosis, hydroureter, and concentric bladder wall thickening despite a lack of urinary distention, suggesting neoplastic infiltration and obstruction of the ureteral outlets. There was significant retroperitoneal lymphadenopathy that was biopsied confirming metastasis of the prostate cancer. He received bilateral nephrostomies and one injection of degarelix followed by maintenance leuprolide every 4 months. His PSA was 420 ng/mL at that time, but rose to 784 ng/mL over the ensuing 2 months. He also had recurrent urinary infections that delayed his systemic treatment. He was started on abiraterone with prednisone.
After 1 month of therapy, his PSA improved to 118 ng/mL but rose again 3 months later to 220 ng/mL when he presented with numerous grouped, flesh-colored, nodulopapular skin lesions on his left lower abdomen, mons pubis, and left flank. Biopsy of these lesions demonstrated poorly differentiated carcinoma with foamy cytoplasm and pyknotic nuclei, expressing PSA and prostate-specific acid phosphatase (PSAP), consistent with metastasis from a high-grade prostatic adenocarcinoma (Figure 2). His treatment was switched to docetaxel with prednisone. After 6 cycles of docetaxel, his skin lesions had regressed. His PSA initially improved but then sharply rose to 481 ng/mL in June 2020 and his chemotherapy was switched to cabazitaxel.
Figure 2. Histological slides obtained from a punch biopsy of a skin lesion demonstrating poorly differentiated carcinoma with sheets of malignant cells and focally microacinar formation on hematoxylin and eosin staining (a). Immunohistochemical staining was positive for AE1/3 (b), weakly positive for prostate-specific antigen (c), and strongly positive for prostate-specific acid phosphatase (d).
Despite 5 cycles of cabazitaxel, his PSA continued to rise to 600 mg/mL, and his cutaneous metastases reappeared. Computed tomography of the abdomen and pelvis demonstrated significant worsening of disease with increased size of liver and lymphatic metastases, along with numerous osteoblastic lesions in the vertebrae. Next-generation sequencing revealed Myc amplification, FGFR1 amplification, and BRCA2 inactivation. However, at that point he had been bed bound for 2 months with contractures, dependent activities of daily living, stage III chronic kidney disease, and recurrent pyelonephritis with extended spectrum β-lactamase positive organisms. He was referred and enrolled in hospice care.
Discussion
This case serves as an example of an unusual presentation of a relatively common disease. Cutaneous metastasis from genitourinary tract carcinomas are rare, most frequently arising from the kidney (66%), followed by the bladder (17%), prostate (12%), and testes (4%).3 Prostate cancer usually first metastasizes to local lymph nodes and bone (hematogenously through Batson’s plexus), followed by lung, liver, and adrenal glands.2,9 If prostate cancer metastases to the skin it is almost always late in its course.3-5 These metastases are usually localized to the abdominopelvic region per literature review, distributed to the inguinal region and penis (28%), abdomen (23%), head and neck (16%), chest (14%), extremities (10%), and back (9%).10
The gross appearance of cutaneous metastases from prostate cancer is highly variable. Skin lesions most often initially present as multiple rubbery nodules or plaques, less often as a single nodule, and uncommonly as edema or a nonspecific rash.10,11 These may be asymptomatic or painful and ulcerated.9,12 Their appearance may resemble zoster, basal cell carcinoma, angiosarcoma, cellulitis, pyoderma gangrenosum, mammary Paget’s disease, telangiectasia, morphea, sebaceous cysts, or trichoepitheliomas.11-13 Biopsy of these lesions is required for definitive diagnosis.
Histological examination of biopsy specimens typically demonstrates acinar adenocarcinoma, but rare variants including atrophic, ductal, xanthomatous, mucinous, signet cell, squamous, urothelial, small cell, or mixed subtypes are possible.14,15 PSA and PSAP are specific to benign or malignant epithelial cells of the prostate gland.15-17 NKX3.1 and prostein (P501s) are highly sensitive and specific, but may also be present in sex cord stromal tumors.17,18 GATA3, p63, 34βE12, thrombomodulin, and cytokeratins (CK) 7 and 20 are often positive in urothelial cancer and typically negative in adenocarcinoma of the prostate.11,15,16 Very poorly differentiated cancers may be exceptional to the aforementioned immunohistochemical staining patterns (eg, PSA negative).15,16 In our case, biopsy of the cutaneous lesions demonstrated strong reactivity for PSAP, minor reactivity for PSA, while both CK7 and CK20 were negative, confirming the nature of the lesions as being metastatic prostate adenocarcinoma.
The route of metastasis of prostate cancer to the skin is not precisely known but may occur through lymphatic or hematogenous spread from the primary tumor with extravasation and invasion of the dermis, direct extension from another site of metastasis, or seeding from a surgical instrument.9,19 Serine proteases such as human tissue kallikreins may play a role in the ability of prostate cancer to infiltrate the skin by breaking down cell-cell adhesions in the epidermis.20 Furthermore, they are involved in the epithelial-mesenchymal transition, a process by which epithelial cells lose their epithelial characteristics and take on those of mesenchymal tissue—a major step in the progression of cancer and a driving factor for metastasis.20
Cutaneous metastases may be treated locally or systemically. Electron radiation therapy has been employed as an effective palliative treatment for painful skin metastases.21,22 Surgical excision and intralesional chemotherapy are also viable options for small and limited metastases.9,10 Systemic chemotherapy has the advantage of potentially reducing the primary malignancy as well as visceral and osseous metastases. According to one review, systemic treatment of the primary malignancy results in at least partial improvement in 65% of cases of cutaneous metastases within 4 to 8 weeks of initiating treatment.9 Our patient’s skin metastases demonstrated a similar response, initially regressing with systemic docetaxel and prednisone and completely disappearing by the second dose. The lesions did not recur until 9 months later when the cancer had stopped responding to taxanes and overall progressed leading to a decline in performance status and enrollment in hospice.
Conclusion
While prostate cancer is the most common cancer affecting men in the United States, metastasis to the skin is very rare and usually indicates advanced disease and a poor prognosis. Factors enabling or promoting cutaneous metastasis may include the human tissue kallikrein family of serine proteases and individual cancer genetics. Localized palliative therapy may be employed for symptomatic cutaneous metastases in select patients; however, systemic therapy is usually preferred. Although initially responsive to androgen deprivation therapy, prostate cancer inevitably becomes castrate resistant. As next-generation sequencing technologies become more widely available personalized therapy targeting specific mutations in an individual cancer is likely to become more commonplace, which may improve outcomes in cases like ours.
Teaching Points
Cutaneous metastasis of urologic cancers, including those of the prostate, are rare and associated with advanced disease and a poor prognosis.
Expression of tissue kallikreins may enhance cancer cell mobilization and facilitate metastatic infiltration of the skin.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases.
Informed Consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
ORCID iD: Alexander Dills
https://orcid.org/0000-0002-8770-7935 | 1 DOSAGE FORM | DrugDosageText | CC BY-NC | 33596692 | 19,062,739 | 2021 |
What was the dosage of drug 'LEUPROLIDE ACETATE'? | Cutaneous Metastasis of Prostate Adenocarcinoma: A Rare Presentation of a Common Disease.
Prostate cancer is the most common cancer affecting men in the United States and the second greatest cause of cancer-related death. Metastases usually occur to bone followed by distant lymph nodes and then viscera. Cutaneous metastases are extremely rare. Their presence indicates advanced disease and a poor prognosis. As they are highly variable in appearance and may mimic a more benign process, biopsy is essential for identification. Serine proteases, particularly human tissue kallikreins, may play an important role in promoting metastasis and facilitate infiltration of the skin. Individual cancer genetics may predispose to more aggressive cancer and thus earlier and more distant metastases. In this article, we report our case of a 67-year-old man with a 4-year history of castrate-resistant prostate cancer with cutaneous metastases confirmed by histology. Despite multiple lines of systemic therapy, the patient suffered progressive disease with worsening performance status and was enrolled in hospice.
Introduction
Prostate cancer is the most common malignancy in men, with an incidence of 106.5 per 100 000 in the United States, and the second most common cause of cancer-related death among American men after lung cancer.1 Common sites of metastasis include bone (84%), lymph nodes (10.6%), liver (10.2%), lung, and pleura (9.1%); however, metastasis to the skin is quite rare (≤0.36%).2-4 Cutaneous metastases tend to occur in the lower abdomen, thighs, and scrotum, but metastasis to chest, back, and face, or as a Sister Mary Joseph nodule have been reported.3-9 When present, it is often late in the course of the disease and considered an ominous sign; patients usually die within a year of its appearance.3-5
Case Description
A 67-year-old man with metastatic castration-resistant prostate cancer presented for evaluation of worsening skin lesions on his lower abdomen and suprapubic area (Figure 1). The patient was initially diagnosed with prostate cancer (Gleason 4 + 5) metastatic to bone in an outside country in June 2016. Prostate-specific antigen (PSA) was 1310 ng/mL at diagnosis, BUN (blood urea nitrogen) was 96 mg/dL, and creatinine was 3.6 mg/dL; all other laboratory values were within normal limits. He was treated with goserelin injections every 3 months with good response for 2 years when his PSA started rising again. He refused systemic treatment at that time. In 2019, he underwent left orchiectomy for a localized seminoma.
Figure 1. Metastasis of prostatic adenocarcinoma presenting as a confluence of reddish nodulopapular skin lesions over the bilateral lower abdomen with extension to the inguinal area and left flank. Left nephrostomy tube is visible.
In June 2019, he received a final dose of goserelin and moved to the United States to be with family and continue treatment. In July 2019, he was admitted for urinary retention and was found to have an acute kidney injury due to obstructive uropathy. Computed tomography of the abdomen and pelvis revealed bilateral hydronephrosis, hydroureter, and concentric bladder wall thickening despite a lack of urinary distention, suggesting neoplastic infiltration and obstruction of the ureteral outlets. There was significant retroperitoneal lymphadenopathy that was biopsied confirming metastasis of the prostate cancer. He received bilateral nephrostomies and one injection of degarelix followed by maintenance leuprolide every 4 months. His PSA was 420 ng/mL at that time, but rose to 784 ng/mL over the ensuing 2 months. He also had recurrent urinary infections that delayed his systemic treatment. He was started on abiraterone with prednisone.
After 1 month of therapy, his PSA improved to 118 ng/mL but rose again 3 months later to 220 ng/mL when he presented with numerous grouped, flesh-colored, nodulopapular skin lesions on his left lower abdomen, mons pubis, and left flank. Biopsy of these lesions demonstrated poorly differentiated carcinoma with foamy cytoplasm and pyknotic nuclei, expressing PSA and prostate-specific acid phosphatase (PSAP), consistent with metastasis from a high-grade prostatic adenocarcinoma (Figure 2). His treatment was switched to docetaxel with prednisone. After 6 cycles of docetaxel, his skin lesions had regressed. His PSA initially improved but then sharply rose to 481 ng/mL in June 2020 and his chemotherapy was switched to cabazitaxel.
Figure 2. Histological slides obtained from a punch biopsy of a skin lesion demonstrating poorly differentiated carcinoma with sheets of malignant cells and focally microacinar formation on hematoxylin and eosin staining (a). Immunohistochemical staining was positive for AE1/3 (b), weakly positive for prostate-specific antigen (c), and strongly positive for prostate-specific acid phosphatase (d).
Despite 5 cycles of cabazitaxel, his PSA continued to rise to 600 mg/mL, and his cutaneous metastases reappeared. Computed tomography of the abdomen and pelvis demonstrated significant worsening of disease with increased size of liver and lymphatic metastases, along with numerous osteoblastic lesions in the vertebrae. Next-generation sequencing revealed Myc amplification, FGFR1 amplification, and BRCA2 inactivation. However, at that point he had been bed bound for 2 months with contractures, dependent activities of daily living, stage III chronic kidney disease, and recurrent pyelonephritis with extended spectrum β-lactamase positive organisms. He was referred and enrolled in hospice care.
Discussion
This case serves as an example of an unusual presentation of a relatively common disease. Cutaneous metastasis from genitourinary tract carcinomas are rare, most frequently arising from the kidney (66%), followed by the bladder (17%), prostate (12%), and testes (4%).3 Prostate cancer usually first metastasizes to local lymph nodes and bone (hematogenously through Batson’s plexus), followed by lung, liver, and adrenal glands.2,9 If prostate cancer metastases to the skin it is almost always late in its course.3-5 These metastases are usually localized to the abdominopelvic region per literature review, distributed to the inguinal region and penis (28%), abdomen (23%), head and neck (16%), chest (14%), extremities (10%), and back (9%).10
The gross appearance of cutaneous metastases from prostate cancer is highly variable. Skin lesions most often initially present as multiple rubbery nodules or plaques, less often as a single nodule, and uncommonly as edema or a nonspecific rash.10,11 These may be asymptomatic or painful and ulcerated.9,12 Their appearance may resemble zoster, basal cell carcinoma, angiosarcoma, cellulitis, pyoderma gangrenosum, mammary Paget’s disease, telangiectasia, morphea, sebaceous cysts, or trichoepitheliomas.11-13 Biopsy of these lesions is required for definitive diagnosis.
Histological examination of biopsy specimens typically demonstrates acinar adenocarcinoma, but rare variants including atrophic, ductal, xanthomatous, mucinous, signet cell, squamous, urothelial, small cell, or mixed subtypes are possible.14,15 PSA and PSAP are specific to benign or malignant epithelial cells of the prostate gland.15-17 NKX3.1 and prostein (P501s) are highly sensitive and specific, but may also be present in sex cord stromal tumors.17,18 GATA3, p63, 34βE12, thrombomodulin, and cytokeratins (CK) 7 and 20 are often positive in urothelial cancer and typically negative in adenocarcinoma of the prostate.11,15,16 Very poorly differentiated cancers may be exceptional to the aforementioned immunohistochemical staining patterns (eg, PSA negative).15,16 In our case, biopsy of the cutaneous lesions demonstrated strong reactivity for PSAP, minor reactivity for PSA, while both CK7 and CK20 were negative, confirming the nature of the lesions as being metastatic prostate adenocarcinoma.
The route of metastasis of prostate cancer to the skin is not precisely known but may occur through lymphatic or hematogenous spread from the primary tumor with extravasation and invasion of the dermis, direct extension from another site of metastasis, or seeding from a surgical instrument.9,19 Serine proteases such as human tissue kallikreins may play a role in the ability of prostate cancer to infiltrate the skin by breaking down cell-cell adhesions in the epidermis.20 Furthermore, they are involved in the epithelial-mesenchymal transition, a process by which epithelial cells lose their epithelial characteristics and take on those of mesenchymal tissue—a major step in the progression of cancer and a driving factor for metastasis.20
Cutaneous metastases may be treated locally or systemically. Electron radiation therapy has been employed as an effective palliative treatment for painful skin metastases.21,22 Surgical excision and intralesional chemotherapy are also viable options for small and limited metastases.9,10 Systemic chemotherapy has the advantage of potentially reducing the primary malignancy as well as visceral and osseous metastases. According to one review, systemic treatment of the primary malignancy results in at least partial improvement in 65% of cases of cutaneous metastases within 4 to 8 weeks of initiating treatment.9 Our patient’s skin metastases demonstrated a similar response, initially regressing with systemic docetaxel and prednisone and completely disappearing by the second dose. The lesions did not recur until 9 months later when the cancer had stopped responding to taxanes and overall progressed leading to a decline in performance status and enrollment in hospice.
Conclusion
While prostate cancer is the most common cancer affecting men in the United States, metastasis to the skin is very rare and usually indicates advanced disease and a poor prognosis. Factors enabling or promoting cutaneous metastasis may include the human tissue kallikrein family of serine proteases and individual cancer genetics. Localized palliative therapy may be employed for symptomatic cutaneous metastases in select patients; however, systemic therapy is usually preferred. Although initially responsive to androgen deprivation therapy, prostate cancer inevitably becomes castrate resistant. As next-generation sequencing technologies become more widely available personalized therapy targeting specific mutations in an individual cancer is likely to become more commonplace, which may improve outcomes in cases like ours.
Teaching Points
Cutaneous metastasis of urologic cancers, including those of the prostate, are rare and associated with advanced disease and a poor prognosis.
Expression of tissue kallikreins may enhance cancer cell mobilization and facilitate metastatic infiltration of the skin.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases.
Informed Consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
ORCID iD: Alexander Dills
https://orcid.org/0000-0002-8770-7935 | UNK, Q 4 MONTH | DrugDosageText | CC BY-NC | 33596692 | 19,062,739 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anti-neutrophil cytoplasmic antibody positive vasculitis'. | Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report.
The relationship between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. A 66-year-old man presented with pulmonary nodules. Histological examination of a specimen from computed tomography-guided percutaneous transthoracic biopsy revealed adenocarcinoma. The patient was treated using cryoablation and systemic chemotherapy. Sixteen months later, the patient presented with fever, nasal inflammation, recurrent lung lesions, elevated serum creatinine levels, and high levels of ANCA. Histological examination of a specimen from ultrasound-guided percutaneous renal biopsy revealed pauci-immune necrotizing crescentic glomerulonephritis. The patient responded to treatment, but granulomatosis with polyangiitis recurred and he later died. This case highlights the possibility of sequential AAV with lung cancer. Although this is relatively rare, further research is needed to better understand the association or pathophysiological link between lung cancer and AAV.
Introduction
The association between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. Some studies have suggested an association or causative link between cancer and AAV,1–3 because AAV can occur in conjunction with other autoimmune diseases and is treated using immunosuppressive therapy,1,3–5 and cancer may be a potential risk factor for AAV.2
There are few reported cases of lung cancer diagnosed before, concurrently, or after AAV.1,2 Here, we present the case of a patient with lung adenocarcinoma who was treated using cryoablation and chemotherapy. The patient subsequently developed granulomatosis with polyangiitis (GPA) that presented as fever, nasal inflammation, and recurrent lung lesions, along with elevated levels of ANCAs and serum creatinine.
Case presentation
This study was approved by the Ethics Committee of The Sixth Medical Center of PLA General Hospital (approval no. HJQX2013-6-1). All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The patient consented to treatment before the initiation of any kind of treatment or procedure. Written informed consent to participate in this study and to publish images or data included in this article was obtained from the patient.
In 2011, a 66-year-old man presented with pulmonary nodules. After 2 years of active monitoring, the pulmonary nodules began to increase in size. The patient developed a mild cough with a small amount of bloody sputum. He had smoked 1.5 packs of cigarettes a day for the past 30 years and denied any family history of cancer or autoimmune diseases. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed metabolically active lesions with intense FDG uptake in the bilateral upper lung lobes (Figure 1). Computed tomography (CT)-guided percutaneous transthoracic biopsy was performed on the mass in the left upper lobe (Figure 2A). Pathological testing identified the mass as stage T2aN3M1a (grade IV) adenocarcinoma (Figure 2B) with no genomic mutations. Laboratory testing showed a C-reactive protein level of 5.1 mg/L (reference range: 0–8 mg/L) and a serum creatinine level of 94 µmol/L (reference range: 62–115 µmol/L); a urinalysis was normal. In April 2013, the patient underwent cryoablation of the bilateral upper lobe lesions (Figure 3A a and b). In May and September 2013, the patient underwent six cycles of paclitaxel and cisplatin chemotherapy.
Figure 1. Positron emission tomography (PET)/computed tomography (CT) revealed bilateral hypermetabolic lung lesions. (a) A CT revealed two nodules in the bilateral upper lung lobes. (b) PET imaging indicated abnormal fluorodeoxyglucose (FDG) uptake in the nodules. (c) A 3-dimensional maximum intensity projection reconstruction of the PET images demonstrated abnormal FDG uptake in the lung and lymph nodes.
Figure 2. Computed tomography (CT)-guided percutaneous transthoracic lung biopsy showing adenocarcinoma. (a) A CT-guided percutaneous transthoracic needle biopsy was performed on the mass in the left upper lobe. (b) Histopathology (hematoxylin and eosin staining) revealed adenocarcinoma.
Figure 3. Lung masses and lesions after computed tomography (CT)-guided cryoablation and chemotherapy. (a) CT after cryoablation of the mass in the left upper lung lobe (a, April 2013), the nodule in the right upper lung lobe (b, April 2013), and the nodule in the left upper lung lobe (c, May 2014). (b) The lung lesions were evaluated after cryoablation and chemotherapy, showing that the right upper lobe lesion had decreased in size, whereas the left upper lobe nodule had not (a and b, May 2014). Follow-up in October 2015 showed that both lesions, in the left and right upper lobes, had decreased in size (c and d).
In May 2014, the patient was referred to our center. Thoracic CT showed that the lesion in the left upper lobe had not markedly decreased in size (Figure 3B a and b). A third round of cryoablation was performed (Figure 3A c). Follow-up over a 6-month period with thoracic CT indicated that the tumor was clinically stable (Figure 3B c and d).
In September 2015, the patient presented with a stuffy nose, orbital and cheek pain, intermittent fever, and an axillary temperature of 37.2 to 39°C. Sinus CT demonstrated left sinusitis (Figure 4A and B). The patient was admitted to the otolaryngology department for sinus surgery. Histopathology confirmed sinusitis (Figure 4C) but the patient’s fever persisted.
Figure 4. Sinus computed tomography (CT) and hematoxylin and eosin-stained sections. Sinus coronal (a) and axial (b) CT images revealed soft tissue filling in the left maxillary sinus, with additional soft tissue in the bilateral ethmoid sinus and right maxillary sinus. (c) Histopathology after sinus surgery (hematoxylin and eosin staining) indicated sinusitis.
In November 2015, thoracic CT revealed new nodules in the right lung lobe (Figure 5A). Blood tests showed a serum creatinine level of 132.1 µmol/L, proteinuria (1765 mg/24 hours; reference range: 0–150 mg/24 hours) with hematuria, an elevated PR3-ANCA titer (423.6 relative units [RU]/mL; reference range: 0–20 RU/mL), and negative results on antiglomerular basement membrane testing. Histopathology of an ultrasound-guided percutaneous renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis (Figure 6). The diagnosis was AAV and GPA with renal, nose, and lung involvement. The patient received corticosteroids (intravenous methylprednisolone, 250 mg, once daily for 3 days, then oral methylprednisolone, 0.5 mg/kg, once daily and reduced by 8 mg every 4 weeks), plasmapheresis (six times in November and December 2015), intravenous cyclophosphamide (600 mg on Day 1 and 400 mg on Day 4, every 5 weeks, eight times, for a cumulative dose of 8000 mg), and methylprednisolone maintenance therapy (oral methylprednisolone, 10 mg, once daily). Following treatment, the patient’s fever subsided. In July 2016, thoracic CT revealed that the pulmonary lesions and new nodules had decreased in size or disappeared (Figure 5B). By January 2017, the patient’s PR3-ANCA titer had decreased to 106.5 RU/mL. The patient did not relapse while receiving cyclophosphamide, and oral methylprednisolone sustained remission.
Figure 5. New nodules in the right lung in November 2015. (A) Chest computed tomography (CT) revealed new nodules in the right lung (a–d). (B) The nodules disappeared (a–d) after treatment using corticosteroids, plasmapheresis, and intravenous cyclophosphamide, followed by maintenance therapy with methylprednisolone.
Figure 6. Histological examination (hematoxylin and eosin staining) of the ultrasound-guided percutaneous renal biopsy specimen revealed pauci-immune necrotizing crescentic glomerulonephritis.
In May 2017, the patient was readmitted for cough with sputum and fever. Laboratory testing showed a white blood cell count of 13.2 × 109/L (reference range: 3.97–9.15 × 109/L), a C-reactive protein level of 132.7 mg/L, a serum creatinine level of 280.3 µmol/L, and an elevated PR3-ANCA titer (366.4 RU/mL). Urinalysis demonstrated proteinuria (676.4 mg/24 hours) with microscopic hematuria. Thoracic CT revealed new lesions and pulmonary cavities in the bilateral lobes (Figure 7). The diagnosis was relapsing GPA with renal and pulmonary involvement and pulmonary infection. Progression of lung cancer could not be completely excluded, but the patient declined a biopsy. The patient was treated with antibiotics, antifungal agents, intravenous methylprednisolone, hemodialysis, and plasmapheresis, but his condition did not improve. A few days later, the patient experienced atrial tachycardia and lost consciousness; cardiopulmonary resuscitation was performed. The patient did not respond to treatment and subsequently died. The patient’s family refused autopsy; therefore, the possibility of lung cancer recurrence could not be excluded.
Figure 7. Chest computed tomography (CT) revealed new bilateral lung lesions in May 2017.
Discussion
There is increasing awareness of the association between malignant and autoimmune diseases in clinical practice.6 Cancer may increase the risk of some autoimmune diseases, and patients with autoimmune diseases may be at a higher risk for cancer.7,8 The mechanism underlying the bidirectional relationship between cancer and autoimmune diseases has yet to be elucidated.
AAV is an autoimmune disease that typically involves the upper and lower respiratory tract and kidney. Malignancy-associated vasculitis accounts for 0.4% to 4.2% of vasculitis cases.9–11 Previous studies have shown that solid tumors and lymphoid and myeloid cancers can develop in patients with circulating ANCA.2,9,12–14 Immunosuppressive treatment for AAV may accelerate the progression of malignant disease through immune suppression or by facilitating tumor immune evasion. Although rare, some reports have described the development of pulmonary malignant diseases in patients treated for AAV.15,16 In the present case, AAV manifested after pre-existing cancer. The initial presentation included pulmonary nodules, which were diagnosed as lung adenocarcinoma on the basis of histopathology. Malignant disease was controlled by cryoablation and chemotherapy; subsequently, the patient showed clinical signs and symptoms of AAV. Other reports have described lung cancer preceding or coinciding with autoimmune diseases such as IgA vasculitis, pauci-immune necrotizing crescentic glomerulonephritis, and sarcoidosis.17–20 The mechanisms by which cancer results in vasculitis are complex. Some speculate that tumors provoke inflammation, which may increase the risk of vasculitis in patients with cancer.9,10,12,13 In the present case, the chemotherapy administered to treat the cancer likely predisposed the patient to AAV. Several other reports describe chemotherapy-associated vasculitis in patients treated for a pre-existing cancer.21,22
Differentiating pulmonary manifestations of GPA from malignant lung lesions using thoracic CT is challenging. FDG-PET/CT imaging is an accurate tool for characterizing pulmonary nodules;23 however, inflammatory lung lesions can mimic malignant tumors by presenting with similar hypermetabolic activity on FDG-PET/CT,24 and this approach alone cannot be used to differentiate between inflammatory and malignant lesions in patients with GPA.25 We recommend that PET/CT be used in combination with a clinical examination and laboratory testing to reach the correct diagnosis. In the present case, PET/CT revealed increased FDG uptake in the bilateral upper lung lesions and enlarged mediastinal and right hilar lymph nodes, which supported the suspected diagnosis of malignancy. Despite this, a diagnosis of lung cancer did not completely explain the findings on pulmonary imaging and biopsy or the entirety of the patient’s clinical course. Therefore, we assumed that vasculitis was present before the pulmonary nodules developed, although there was no kidney involvement at that time. The patient initially underwent CT-guided percutaneous transthoracic lung biopsy for the mass in the left upper lobe. The diagnosis of lung cancer was confirmed, but the procedure provided a relatively small sample, and it is possible that the vasculitis could not have been seen in that specimen. Previous studies have suggested that transthoracic fine-needle aspiration may not be sufficiently accurate for diagnosing GPA with lung involvement.26,27 In one report, a lung nodule removed using video-assisted thoracoscopic surgery was pathologically diagnosed as concurrent GPA and lung squamous carcinoma.28 The characteristics of the right and left lung masses may have been inconsistent, and we did not repeat the biopsy for the mass in the right upper lobe to gain additional information regarding a diagnosis of vasculitis. Importantly, PET/CT did reveal soft tissue in the patient’s left sinuses, which did not exhibit increased FDG uptake (Figure 8). We interpreted these findings as suspected vasculitis in the nose. Finally, the bilateral lung lesions did not significantly decrease in size after chemotherapy and cryoablation, but the left lung mass decreased in size and the right lung mass and new nodules disappeared after treatment using corticosteroids and intravenous cyclophosphamide. Thus, it is possible that the bilateral lung lesions were related to vasculitis. Unfortunately, the patient died after experiencing relapsing GPA with renal complications and pulmonary infection.
Figure 8. Computed tomography (CT) revealed left sinusitis. (a) CT revealed mild mucosal thickening in the ethmoid, sphenoid, and left maxillary sinus. (b) Positron emission tomography showed no remarkable fluorodeoxyglucose uptake in the sinuses.
To our knowledge, this is the first published report of lung adenocarcinoma and granulomatous polyangiitis. These findings add to the clinical knowledge regarding the concurrent occurrence of malignant diseases and autoimmune diseases. Further research is required to understand the pathophysiological link between cancer and autoimmune diseases.
Supplemental Material
sj-pdf-1-imr-10.1177_0300060521993319 - Supplemental material for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report
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Supplemental material, sj-pdf-1-imr-10.1177_0300060521993319 for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report by Chun-Yang Zhang, Ran Miao, Wei Li, Hao-Yong Ning, Xiang-En Meng, Zhi-Hai Han, Feng Qin, Ying-Kui Liang and Ming-Xv Li in Journal of International Medical Research
Declaration of conflicting interests: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Ying-Kui Liang https://orcid.org/0000-0003-1393-1587 | CISPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY-NC | 33596705 | 19,074,494 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Glomerulonephritis rapidly progressive'. | Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report.
The relationship between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. A 66-year-old man presented with pulmonary nodules. Histological examination of a specimen from computed tomography-guided percutaneous transthoracic biopsy revealed adenocarcinoma. The patient was treated using cryoablation and systemic chemotherapy. Sixteen months later, the patient presented with fever, nasal inflammation, recurrent lung lesions, elevated serum creatinine levels, and high levels of ANCA. Histological examination of a specimen from ultrasound-guided percutaneous renal biopsy revealed pauci-immune necrotizing crescentic glomerulonephritis. The patient responded to treatment, but granulomatosis with polyangiitis recurred and he later died. This case highlights the possibility of sequential AAV with lung cancer. Although this is relatively rare, further research is needed to better understand the association or pathophysiological link between lung cancer and AAV.
Introduction
The association between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. Some studies have suggested an association or causative link between cancer and AAV,1–3 because AAV can occur in conjunction with other autoimmune diseases and is treated using immunosuppressive therapy,1,3–5 and cancer may be a potential risk factor for AAV.2
There are few reported cases of lung cancer diagnosed before, concurrently, or after AAV.1,2 Here, we present the case of a patient with lung adenocarcinoma who was treated using cryoablation and chemotherapy. The patient subsequently developed granulomatosis with polyangiitis (GPA) that presented as fever, nasal inflammation, and recurrent lung lesions, along with elevated levels of ANCAs and serum creatinine.
Case presentation
This study was approved by the Ethics Committee of The Sixth Medical Center of PLA General Hospital (approval no. HJQX2013-6-1). All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The patient consented to treatment before the initiation of any kind of treatment or procedure. Written informed consent to participate in this study and to publish images or data included in this article was obtained from the patient.
In 2011, a 66-year-old man presented with pulmonary nodules. After 2 years of active monitoring, the pulmonary nodules began to increase in size. The patient developed a mild cough with a small amount of bloody sputum. He had smoked 1.5 packs of cigarettes a day for the past 30 years and denied any family history of cancer or autoimmune diseases. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed metabolically active lesions with intense FDG uptake in the bilateral upper lung lobes (Figure 1). Computed tomography (CT)-guided percutaneous transthoracic biopsy was performed on the mass in the left upper lobe (Figure 2A). Pathological testing identified the mass as stage T2aN3M1a (grade IV) adenocarcinoma (Figure 2B) with no genomic mutations. Laboratory testing showed a C-reactive protein level of 5.1 mg/L (reference range: 0–8 mg/L) and a serum creatinine level of 94 µmol/L (reference range: 62–115 µmol/L); a urinalysis was normal. In April 2013, the patient underwent cryoablation of the bilateral upper lobe lesions (Figure 3A a and b). In May and September 2013, the patient underwent six cycles of paclitaxel and cisplatin chemotherapy.
Figure 1. Positron emission tomography (PET)/computed tomography (CT) revealed bilateral hypermetabolic lung lesions. (a) A CT revealed two nodules in the bilateral upper lung lobes. (b) PET imaging indicated abnormal fluorodeoxyglucose (FDG) uptake in the nodules. (c) A 3-dimensional maximum intensity projection reconstruction of the PET images demonstrated abnormal FDG uptake in the lung and lymph nodes.
Figure 2. Computed tomography (CT)-guided percutaneous transthoracic lung biopsy showing adenocarcinoma. (a) A CT-guided percutaneous transthoracic needle biopsy was performed on the mass in the left upper lobe. (b) Histopathology (hematoxylin and eosin staining) revealed adenocarcinoma.
Figure 3. Lung masses and lesions after computed tomography (CT)-guided cryoablation and chemotherapy. (a) CT after cryoablation of the mass in the left upper lung lobe (a, April 2013), the nodule in the right upper lung lobe (b, April 2013), and the nodule in the left upper lung lobe (c, May 2014). (b) The lung lesions were evaluated after cryoablation and chemotherapy, showing that the right upper lobe lesion had decreased in size, whereas the left upper lobe nodule had not (a and b, May 2014). Follow-up in October 2015 showed that both lesions, in the left and right upper lobes, had decreased in size (c and d).
In May 2014, the patient was referred to our center. Thoracic CT showed that the lesion in the left upper lobe had not markedly decreased in size (Figure 3B a and b). A third round of cryoablation was performed (Figure 3A c). Follow-up over a 6-month period with thoracic CT indicated that the tumor was clinically stable (Figure 3B c and d).
In September 2015, the patient presented with a stuffy nose, orbital and cheek pain, intermittent fever, and an axillary temperature of 37.2 to 39°C. Sinus CT demonstrated left sinusitis (Figure 4A and B). The patient was admitted to the otolaryngology department for sinus surgery. Histopathology confirmed sinusitis (Figure 4C) but the patient’s fever persisted.
Figure 4. Sinus computed tomography (CT) and hematoxylin and eosin-stained sections. Sinus coronal (a) and axial (b) CT images revealed soft tissue filling in the left maxillary sinus, with additional soft tissue in the bilateral ethmoid sinus and right maxillary sinus. (c) Histopathology after sinus surgery (hematoxylin and eosin staining) indicated sinusitis.
In November 2015, thoracic CT revealed new nodules in the right lung lobe (Figure 5A). Blood tests showed a serum creatinine level of 132.1 µmol/L, proteinuria (1765 mg/24 hours; reference range: 0–150 mg/24 hours) with hematuria, an elevated PR3-ANCA titer (423.6 relative units [RU]/mL; reference range: 0–20 RU/mL), and negative results on antiglomerular basement membrane testing. Histopathology of an ultrasound-guided percutaneous renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis (Figure 6). The diagnosis was AAV and GPA with renal, nose, and lung involvement. The patient received corticosteroids (intravenous methylprednisolone, 250 mg, once daily for 3 days, then oral methylprednisolone, 0.5 mg/kg, once daily and reduced by 8 mg every 4 weeks), plasmapheresis (six times in November and December 2015), intravenous cyclophosphamide (600 mg on Day 1 and 400 mg on Day 4, every 5 weeks, eight times, for a cumulative dose of 8000 mg), and methylprednisolone maintenance therapy (oral methylprednisolone, 10 mg, once daily). Following treatment, the patient’s fever subsided. In July 2016, thoracic CT revealed that the pulmonary lesions and new nodules had decreased in size or disappeared (Figure 5B). By January 2017, the patient’s PR3-ANCA titer had decreased to 106.5 RU/mL. The patient did not relapse while receiving cyclophosphamide, and oral methylprednisolone sustained remission.
Figure 5. New nodules in the right lung in November 2015. (A) Chest computed tomography (CT) revealed new nodules in the right lung (a–d). (B) The nodules disappeared (a–d) after treatment using corticosteroids, plasmapheresis, and intravenous cyclophosphamide, followed by maintenance therapy with methylprednisolone.
Figure 6. Histological examination (hematoxylin and eosin staining) of the ultrasound-guided percutaneous renal biopsy specimen revealed pauci-immune necrotizing crescentic glomerulonephritis.
In May 2017, the patient was readmitted for cough with sputum and fever. Laboratory testing showed a white blood cell count of 13.2 × 109/L (reference range: 3.97–9.15 × 109/L), a C-reactive protein level of 132.7 mg/L, a serum creatinine level of 280.3 µmol/L, and an elevated PR3-ANCA titer (366.4 RU/mL). Urinalysis demonstrated proteinuria (676.4 mg/24 hours) with microscopic hematuria. Thoracic CT revealed new lesions and pulmonary cavities in the bilateral lobes (Figure 7). The diagnosis was relapsing GPA with renal and pulmonary involvement and pulmonary infection. Progression of lung cancer could not be completely excluded, but the patient declined a biopsy. The patient was treated with antibiotics, antifungal agents, intravenous methylprednisolone, hemodialysis, and plasmapheresis, but his condition did not improve. A few days later, the patient experienced atrial tachycardia and lost consciousness; cardiopulmonary resuscitation was performed. The patient did not respond to treatment and subsequently died. The patient’s family refused autopsy; therefore, the possibility of lung cancer recurrence could not be excluded.
Figure 7. Chest computed tomography (CT) revealed new bilateral lung lesions in May 2017.
Discussion
There is increasing awareness of the association between malignant and autoimmune diseases in clinical practice.6 Cancer may increase the risk of some autoimmune diseases, and patients with autoimmune diseases may be at a higher risk for cancer.7,8 The mechanism underlying the bidirectional relationship between cancer and autoimmune diseases has yet to be elucidated.
AAV is an autoimmune disease that typically involves the upper and lower respiratory tract and kidney. Malignancy-associated vasculitis accounts for 0.4% to 4.2% of vasculitis cases.9–11 Previous studies have shown that solid tumors and lymphoid and myeloid cancers can develop in patients with circulating ANCA.2,9,12–14 Immunosuppressive treatment for AAV may accelerate the progression of malignant disease through immune suppression or by facilitating tumor immune evasion. Although rare, some reports have described the development of pulmonary malignant diseases in patients treated for AAV.15,16 In the present case, AAV manifested after pre-existing cancer. The initial presentation included pulmonary nodules, which were diagnosed as lung adenocarcinoma on the basis of histopathology. Malignant disease was controlled by cryoablation and chemotherapy; subsequently, the patient showed clinical signs and symptoms of AAV. Other reports have described lung cancer preceding or coinciding with autoimmune diseases such as IgA vasculitis, pauci-immune necrotizing crescentic glomerulonephritis, and sarcoidosis.17–20 The mechanisms by which cancer results in vasculitis are complex. Some speculate that tumors provoke inflammation, which may increase the risk of vasculitis in patients with cancer.9,10,12,13 In the present case, the chemotherapy administered to treat the cancer likely predisposed the patient to AAV. Several other reports describe chemotherapy-associated vasculitis in patients treated for a pre-existing cancer.21,22
Differentiating pulmonary manifestations of GPA from malignant lung lesions using thoracic CT is challenging. FDG-PET/CT imaging is an accurate tool for characterizing pulmonary nodules;23 however, inflammatory lung lesions can mimic malignant tumors by presenting with similar hypermetabolic activity on FDG-PET/CT,24 and this approach alone cannot be used to differentiate between inflammatory and malignant lesions in patients with GPA.25 We recommend that PET/CT be used in combination with a clinical examination and laboratory testing to reach the correct diagnosis. In the present case, PET/CT revealed increased FDG uptake in the bilateral upper lung lesions and enlarged mediastinal and right hilar lymph nodes, which supported the suspected diagnosis of malignancy. Despite this, a diagnosis of lung cancer did not completely explain the findings on pulmonary imaging and biopsy or the entirety of the patient’s clinical course. Therefore, we assumed that vasculitis was present before the pulmonary nodules developed, although there was no kidney involvement at that time. The patient initially underwent CT-guided percutaneous transthoracic lung biopsy for the mass in the left upper lobe. The diagnosis of lung cancer was confirmed, but the procedure provided a relatively small sample, and it is possible that the vasculitis could not have been seen in that specimen. Previous studies have suggested that transthoracic fine-needle aspiration may not be sufficiently accurate for diagnosing GPA with lung involvement.26,27 In one report, a lung nodule removed using video-assisted thoracoscopic surgery was pathologically diagnosed as concurrent GPA and lung squamous carcinoma.28 The characteristics of the right and left lung masses may have been inconsistent, and we did not repeat the biopsy for the mass in the right upper lobe to gain additional information regarding a diagnosis of vasculitis. Importantly, PET/CT did reveal soft tissue in the patient’s left sinuses, which did not exhibit increased FDG uptake (Figure 8). We interpreted these findings as suspected vasculitis in the nose. Finally, the bilateral lung lesions did not significantly decrease in size after chemotherapy and cryoablation, but the left lung mass decreased in size and the right lung mass and new nodules disappeared after treatment using corticosteroids and intravenous cyclophosphamide. Thus, it is possible that the bilateral lung lesions were related to vasculitis. Unfortunately, the patient died after experiencing relapsing GPA with renal complications and pulmonary infection.
Figure 8. Computed tomography (CT) revealed left sinusitis. (a) CT revealed mild mucosal thickening in the ethmoid, sphenoid, and left maxillary sinus. (b) Positron emission tomography showed no remarkable fluorodeoxyglucose uptake in the sinuses.
To our knowledge, this is the first published report of lung adenocarcinoma and granulomatous polyangiitis. These findings add to the clinical knowledge regarding the concurrent occurrence of malignant diseases and autoimmune diseases. Further research is required to understand the pathophysiological link between cancer and autoimmune diseases.
Supplemental Material
sj-pdf-1-imr-10.1177_0300060521993319 - Supplemental material for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report
Click here for additional data file.
Supplemental material, sj-pdf-1-imr-10.1177_0300060521993319 for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report by Chun-Yang Zhang, Ran Miao, Wei Li, Hao-Yong Ning, Xiang-En Meng, Zhi-Hai Han, Feng Qin, Ying-Kui Liang and Ming-Xv Li in Journal of International Medical Research
Declaration of conflicting interests: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Ying-Kui Liang https://orcid.org/0000-0003-1393-1587 | CISPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY-NC | 33596705 | 19,074,494 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Granulomatosis with polyangiitis'. | Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report.
The relationship between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. A 66-year-old man presented with pulmonary nodules. Histological examination of a specimen from computed tomography-guided percutaneous transthoracic biopsy revealed adenocarcinoma. The patient was treated using cryoablation and systemic chemotherapy. Sixteen months later, the patient presented with fever, nasal inflammation, recurrent lung lesions, elevated serum creatinine levels, and high levels of ANCA. Histological examination of a specimen from ultrasound-guided percutaneous renal biopsy revealed pauci-immune necrotizing crescentic glomerulonephritis. The patient responded to treatment, but granulomatosis with polyangiitis recurred and he later died. This case highlights the possibility of sequential AAV with lung cancer. Although this is relatively rare, further research is needed to better understand the association or pathophysiological link between lung cancer and AAV.
Introduction
The association between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. Some studies have suggested an association or causative link between cancer and AAV,1–3 because AAV can occur in conjunction with other autoimmune diseases and is treated using immunosuppressive therapy,1,3–5 and cancer may be a potential risk factor for AAV.2
There are few reported cases of lung cancer diagnosed before, concurrently, or after AAV.1,2 Here, we present the case of a patient with lung adenocarcinoma who was treated using cryoablation and chemotherapy. The patient subsequently developed granulomatosis with polyangiitis (GPA) that presented as fever, nasal inflammation, and recurrent lung lesions, along with elevated levels of ANCAs and serum creatinine.
Case presentation
This study was approved by the Ethics Committee of The Sixth Medical Center of PLA General Hospital (approval no. HJQX2013-6-1). All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The patient consented to treatment before the initiation of any kind of treatment or procedure. Written informed consent to participate in this study and to publish images or data included in this article was obtained from the patient.
In 2011, a 66-year-old man presented with pulmonary nodules. After 2 years of active monitoring, the pulmonary nodules began to increase in size. The patient developed a mild cough with a small amount of bloody sputum. He had smoked 1.5 packs of cigarettes a day for the past 30 years and denied any family history of cancer or autoimmune diseases. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed metabolically active lesions with intense FDG uptake in the bilateral upper lung lobes (Figure 1). Computed tomography (CT)-guided percutaneous transthoracic biopsy was performed on the mass in the left upper lobe (Figure 2A). Pathological testing identified the mass as stage T2aN3M1a (grade IV) adenocarcinoma (Figure 2B) with no genomic mutations. Laboratory testing showed a C-reactive protein level of 5.1 mg/L (reference range: 0–8 mg/L) and a serum creatinine level of 94 µmol/L (reference range: 62–115 µmol/L); a urinalysis was normal. In April 2013, the patient underwent cryoablation of the bilateral upper lobe lesions (Figure 3A a and b). In May and September 2013, the patient underwent six cycles of paclitaxel and cisplatin chemotherapy.
Figure 1. Positron emission tomography (PET)/computed tomography (CT) revealed bilateral hypermetabolic lung lesions. (a) A CT revealed two nodules in the bilateral upper lung lobes. (b) PET imaging indicated abnormal fluorodeoxyglucose (FDG) uptake in the nodules. (c) A 3-dimensional maximum intensity projection reconstruction of the PET images demonstrated abnormal FDG uptake in the lung and lymph nodes.
Figure 2. Computed tomography (CT)-guided percutaneous transthoracic lung biopsy showing adenocarcinoma. (a) A CT-guided percutaneous transthoracic needle biopsy was performed on the mass in the left upper lobe. (b) Histopathology (hematoxylin and eosin staining) revealed adenocarcinoma.
Figure 3. Lung masses and lesions after computed tomography (CT)-guided cryoablation and chemotherapy. (a) CT after cryoablation of the mass in the left upper lung lobe (a, April 2013), the nodule in the right upper lung lobe (b, April 2013), and the nodule in the left upper lung lobe (c, May 2014). (b) The lung lesions were evaluated after cryoablation and chemotherapy, showing that the right upper lobe lesion had decreased in size, whereas the left upper lobe nodule had not (a and b, May 2014). Follow-up in October 2015 showed that both lesions, in the left and right upper lobes, had decreased in size (c and d).
In May 2014, the patient was referred to our center. Thoracic CT showed that the lesion in the left upper lobe had not markedly decreased in size (Figure 3B a and b). A third round of cryoablation was performed (Figure 3A c). Follow-up over a 6-month period with thoracic CT indicated that the tumor was clinically stable (Figure 3B c and d).
In September 2015, the patient presented with a stuffy nose, orbital and cheek pain, intermittent fever, and an axillary temperature of 37.2 to 39°C. Sinus CT demonstrated left sinusitis (Figure 4A and B). The patient was admitted to the otolaryngology department for sinus surgery. Histopathology confirmed sinusitis (Figure 4C) but the patient’s fever persisted.
Figure 4. Sinus computed tomography (CT) and hematoxylin and eosin-stained sections. Sinus coronal (a) and axial (b) CT images revealed soft tissue filling in the left maxillary sinus, with additional soft tissue in the bilateral ethmoid sinus and right maxillary sinus. (c) Histopathology after sinus surgery (hematoxylin and eosin staining) indicated sinusitis.
In November 2015, thoracic CT revealed new nodules in the right lung lobe (Figure 5A). Blood tests showed a serum creatinine level of 132.1 µmol/L, proteinuria (1765 mg/24 hours; reference range: 0–150 mg/24 hours) with hematuria, an elevated PR3-ANCA titer (423.6 relative units [RU]/mL; reference range: 0–20 RU/mL), and negative results on antiglomerular basement membrane testing. Histopathology of an ultrasound-guided percutaneous renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis (Figure 6). The diagnosis was AAV and GPA with renal, nose, and lung involvement. The patient received corticosteroids (intravenous methylprednisolone, 250 mg, once daily for 3 days, then oral methylprednisolone, 0.5 mg/kg, once daily and reduced by 8 mg every 4 weeks), plasmapheresis (six times in November and December 2015), intravenous cyclophosphamide (600 mg on Day 1 and 400 mg on Day 4, every 5 weeks, eight times, for a cumulative dose of 8000 mg), and methylprednisolone maintenance therapy (oral methylprednisolone, 10 mg, once daily). Following treatment, the patient’s fever subsided. In July 2016, thoracic CT revealed that the pulmonary lesions and new nodules had decreased in size or disappeared (Figure 5B). By January 2017, the patient’s PR3-ANCA titer had decreased to 106.5 RU/mL. The patient did not relapse while receiving cyclophosphamide, and oral methylprednisolone sustained remission.
Figure 5. New nodules in the right lung in November 2015. (A) Chest computed tomography (CT) revealed new nodules in the right lung (a–d). (B) The nodules disappeared (a–d) after treatment using corticosteroids, plasmapheresis, and intravenous cyclophosphamide, followed by maintenance therapy with methylprednisolone.
Figure 6. Histological examination (hematoxylin and eosin staining) of the ultrasound-guided percutaneous renal biopsy specimen revealed pauci-immune necrotizing crescentic glomerulonephritis.
In May 2017, the patient was readmitted for cough with sputum and fever. Laboratory testing showed a white blood cell count of 13.2 × 109/L (reference range: 3.97–9.15 × 109/L), a C-reactive protein level of 132.7 mg/L, a serum creatinine level of 280.3 µmol/L, and an elevated PR3-ANCA titer (366.4 RU/mL). Urinalysis demonstrated proteinuria (676.4 mg/24 hours) with microscopic hematuria. Thoracic CT revealed new lesions and pulmonary cavities in the bilateral lobes (Figure 7). The diagnosis was relapsing GPA with renal and pulmonary involvement and pulmonary infection. Progression of lung cancer could not be completely excluded, but the patient declined a biopsy. The patient was treated with antibiotics, antifungal agents, intravenous methylprednisolone, hemodialysis, and plasmapheresis, but his condition did not improve. A few days later, the patient experienced atrial tachycardia and lost consciousness; cardiopulmonary resuscitation was performed. The patient did not respond to treatment and subsequently died. The patient’s family refused autopsy; therefore, the possibility of lung cancer recurrence could not be excluded.
Figure 7. Chest computed tomography (CT) revealed new bilateral lung lesions in May 2017.
Discussion
There is increasing awareness of the association between malignant and autoimmune diseases in clinical practice.6 Cancer may increase the risk of some autoimmune diseases, and patients with autoimmune diseases may be at a higher risk for cancer.7,8 The mechanism underlying the bidirectional relationship between cancer and autoimmune diseases has yet to be elucidated.
AAV is an autoimmune disease that typically involves the upper and lower respiratory tract and kidney. Malignancy-associated vasculitis accounts for 0.4% to 4.2% of vasculitis cases.9–11 Previous studies have shown that solid tumors and lymphoid and myeloid cancers can develop in patients with circulating ANCA.2,9,12–14 Immunosuppressive treatment for AAV may accelerate the progression of malignant disease through immune suppression or by facilitating tumor immune evasion. Although rare, some reports have described the development of pulmonary malignant diseases in patients treated for AAV.15,16 In the present case, AAV manifested after pre-existing cancer. The initial presentation included pulmonary nodules, which were diagnosed as lung adenocarcinoma on the basis of histopathology. Malignant disease was controlled by cryoablation and chemotherapy; subsequently, the patient showed clinical signs and symptoms of AAV. Other reports have described lung cancer preceding or coinciding with autoimmune diseases such as IgA vasculitis, pauci-immune necrotizing crescentic glomerulonephritis, and sarcoidosis.17–20 The mechanisms by which cancer results in vasculitis are complex. Some speculate that tumors provoke inflammation, which may increase the risk of vasculitis in patients with cancer.9,10,12,13 In the present case, the chemotherapy administered to treat the cancer likely predisposed the patient to AAV. Several other reports describe chemotherapy-associated vasculitis in patients treated for a pre-existing cancer.21,22
Differentiating pulmonary manifestations of GPA from malignant lung lesions using thoracic CT is challenging. FDG-PET/CT imaging is an accurate tool for characterizing pulmonary nodules;23 however, inflammatory lung lesions can mimic malignant tumors by presenting with similar hypermetabolic activity on FDG-PET/CT,24 and this approach alone cannot be used to differentiate between inflammatory and malignant lesions in patients with GPA.25 We recommend that PET/CT be used in combination with a clinical examination and laboratory testing to reach the correct diagnosis. In the present case, PET/CT revealed increased FDG uptake in the bilateral upper lung lesions and enlarged mediastinal and right hilar lymph nodes, which supported the suspected diagnosis of malignancy. Despite this, a diagnosis of lung cancer did not completely explain the findings on pulmonary imaging and biopsy or the entirety of the patient’s clinical course. Therefore, we assumed that vasculitis was present before the pulmonary nodules developed, although there was no kidney involvement at that time. The patient initially underwent CT-guided percutaneous transthoracic lung biopsy for the mass in the left upper lobe. The diagnosis of lung cancer was confirmed, but the procedure provided a relatively small sample, and it is possible that the vasculitis could not have been seen in that specimen. Previous studies have suggested that transthoracic fine-needle aspiration may not be sufficiently accurate for diagnosing GPA with lung involvement.26,27 In one report, a lung nodule removed using video-assisted thoracoscopic surgery was pathologically diagnosed as concurrent GPA and lung squamous carcinoma.28 The characteristics of the right and left lung masses may have been inconsistent, and we did not repeat the biopsy for the mass in the right upper lobe to gain additional information regarding a diagnosis of vasculitis. Importantly, PET/CT did reveal soft tissue in the patient’s left sinuses, which did not exhibit increased FDG uptake (Figure 8). We interpreted these findings as suspected vasculitis in the nose. Finally, the bilateral lung lesions did not significantly decrease in size after chemotherapy and cryoablation, but the left lung mass decreased in size and the right lung mass and new nodules disappeared after treatment using corticosteroids and intravenous cyclophosphamide. Thus, it is possible that the bilateral lung lesions were related to vasculitis. Unfortunately, the patient died after experiencing relapsing GPA with renal complications and pulmonary infection.
Figure 8. Computed tomography (CT) revealed left sinusitis. (a) CT revealed mild mucosal thickening in the ethmoid, sphenoid, and left maxillary sinus. (b) Positron emission tomography showed no remarkable fluorodeoxyglucose uptake in the sinuses.
To our knowledge, this is the first published report of lung adenocarcinoma and granulomatous polyangiitis. These findings add to the clinical knowledge regarding the concurrent occurrence of malignant diseases and autoimmune diseases. Further research is required to understand the pathophysiological link between cancer and autoimmune diseases.
Supplemental Material
sj-pdf-1-imr-10.1177_0300060521993319 - Supplemental material for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report
Click here for additional data file.
Supplemental material, sj-pdf-1-imr-10.1177_0300060521993319 for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report by Chun-Yang Zhang, Ran Miao, Wei Li, Hao-Yong Ning, Xiang-En Meng, Zhi-Hai Han, Feng Qin, Ying-Kui Liang and Ming-Xv Li in Journal of International Medical Research
Declaration of conflicting interests: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Ying-Kui Liang https://orcid.org/0000-0003-1393-1587 | CISPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY-NC | 33596705 | 19,074,494 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary granuloma'. | Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report.
The relationship between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. A 66-year-old man presented with pulmonary nodules. Histological examination of a specimen from computed tomography-guided percutaneous transthoracic biopsy revealed adenocarcinoma. The patient was treated using cryoablation and systemic chemotherapy. Sixteen months later, the patient presented with fever, nasal inflammation, recurrent lung lesions, elevated serum creatinine levels, and high levels of ANCA. Histological examination of a specimen from ultrasound-guided percutaneous renal biopsy revealed pauci-immune necrotizing crescentic glomerulonephritis. The patient responded to treatment, but granulomatosis with polyangiitis recurred and he later died. This case highlights the possibility of sequential AAV with lung cancer. Although this is relatively rare, further research is needed to better understand the association or pathophysiological link between lung cancer and AAV.
Introduction
The association between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. Some studies have suggested an association or causative link between cancer and AAV,1–3 because AAV can occur in conjunction with other autoimmune diseases and is treated using immunosuppressive therapy,1,3–5 and cancer may be a potential risk factor for AAV.2
There are few reported cases of lung cancer diagnosed before, concurrently, or after AAV.1,2 Here, we present the case of a patient with lung adenocarcinoma who was treated using cryoablation and chemotherapy. The patient subsequently developed granulomatosis with polyangiitis (GPA) that presented as fever, nasal inflammation, and recurrent lung lesions, along with elevated levels of ANCAs and serum creatinine.
Case presentation
This study was approved by the Ethics Committee of The Sixth Medical Center of PLA General Hospital (approval no. HJQX2013-6-1). All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The patient consented to treatment before the initiation of any kind of treatment or procedure. Written informed consent to participate in this study and to publish images or data included in this article was obtained from the patient.
In 2011, a 66-year-old man presented with pulmonary nodules. After 2 years of active monitoring, the pulmonary nodules began to increase in size. The patient developed a mild cough with a small amount of bloody sputum. He had smoked 1.5 packs of cigarettes a day for the past 30 years and denied any family history of cancer or autoimmune diseases. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed metabolically active lesions with intense FDG uptake in the bilateral upper lung lobes (Figure 1). Computed tomography (CT)-guided percutaneous transthoracic biopsy was performed on the mass in the left upper lobe (Figure 2A). Pathological testing identified the mass as stage T2aN3M1a (grade IV) adenocarcinoma (Figure 2B) with no genomic mutations. Laboratory testing showed a C-reactive protein level of 5.1 mg/L (reference range: 0–8 mg/L) and a serum creatinine level of 94 µmol/L (reference range: 62–115 µmol/L); a urinalysis was normal. In April 2013, the patient underwent cryoablation of the bilateral upper lobe lesions (Figure 3A a and b). In May and September 2013, the patient underwent six cycles of paclitaxel and cisplatin chemotherapy.
Figure 1. Positron emission tomography (PET)/computed tomography (CT) revealed bilateral hypermetabolic lung lesions. (a) A CT revealed two nodules in the bilateral upper lung lobes. (b) PET imaging indicated abnormal fluorodeoxyglucose (FDG) uptake in the nodules. (c) A 3-dimensional maximum intensity projection reconstruction of the PET images demonstrated abnormal FDG uptake in the lung and lymph nodes.
Figure 2. Computed tomography (CT)-guided percutaneous transthoracic lung biopsy showing adenocarcinoma. (a) A CT-guided percutaneous transthoracic needle biopsy was performed on the mass in the left upper lobe. (b) Histopathology (hematoxylin and eosin staining) revealed adenocarcinoma.
Figure 3. Lung masses and lesions after computed tomography (CT)-guided cryoablation and chemotherapy. (a) CT after cryoablation of the mass in the left upper lung lobe (a, April 2013), the nodule in the right upper lung lobe (b, April 2013), and the nodule in the left upper lung lobe (c, May 2014). (b) The lung lesions were evaluated after cryoablation and chemotherapy, showing that the right upper lobe lesion had decreased in size, whereas the left upper lobe nodule had not (a and b, May 2014). Follow-up in October 2015 showed that both lesions, in the left and right upper lobes, had decreased in size (c and d).
In May 2014, the patient was referred to our center. Thoracic CT showed that the lesion in the left upper lobe had not markedly decreased in size (Figure 3B a and b). A third round of cryoablation was performed (Figure 3A c). Follow-up over a 6-month period with thoracic CT indicated that the tumor was clinically stable (Figure 3B c and d).
In September 2015, the patient presented with a stuffy nose, orbital and cheek pain, intermittent fever, and an axillary temperature of 37.2 to 39°C. Sinus CT demonstrated left sinusitis (Figure 4A and B). The patient was admitted to the otolaryngology department for sinus surgery. Histopathology confirmed sinusitis (Figure 4C) but the patient’s fever persisted.
Figure 4. Sinus computed tomography (CT) and hematoxylin and eosin-stained sections. Sinus coronal (a) and axial (b) CT images revealed soft tissue filling in the left maxillary sinus, with additional soft tissue in the bilateral ethmoid sinus and right maxillary sinus. (c) Histopathology after sinus surgery (hematoxylin and eosin staining) indicated sinusitis.
In November 2015, thoracic CT revealed new nodules in the right lung lobe (Figure 5A). Blood tests showed a serum creatinine level of 132.1 µmol/L, proteinuria (1765 mg/24 hours; reference range: 0–150 mg/24 hours) with hematuria, an elevated PR3-ANCA titer (423.6 relative units [RU]/mL; reference range: 0–20 RU/mL), and negative results on antiglomerular basement membrane testing. Histopathology of an ultrasound-guided percutaneous renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis (Figure 6). The diagnosis was AAV and GPA with renal, nose, and lung involvement. The patient received corticosteroids (intravenous methylprednisolone, 250 mg, once daily for 3 days, then oral methylprednisolone, 0.5 mg/kg, once daily and reduced by 8 mg every 4 weeks), plasmapheresis (six times in November and December 2015), intravenous cyclophosphamide (600 mg on Day 1 and 400 mg on Day 4, every 5 weeks, eight times, for a cumulative dose of 8000 mg), and methylprednisolone maintenance therapy (oral methylprednisolone, 10 mg, once daily). Following treatment, the patient’s fever subsided. In July 2016, thoracic CT revealed that the pulmonary lesions and new nodules had decreased in size or disappeared (Figure 5B). By January 2017, the patient’s PR3-ANCA titer had decreased to 106.5 RU/mL. The patient did not relapse while receiving cyclophosphamide, and oral methylprednisolone sustained remission.
Figure 5. New nodules in the right lung in November 2015. (A) Chest computed tomography (CT) revealed new nodules in the right lung (a–d). (B) The nodules disappeared (a–d) after treatment using corticosteroids, plasmapheresis, and intravenous cyclophosphamide, followed by maintenance therapy with methylprednisolone.
Figure 6. Histological examination (hematoxylin and eosin staining) of the ultrasound-guided percutaneous renal biopsy specimen revealed pauci-immune necrotizing crescentic glomerulonephritis.
In May 2017, the patient was readmitted for cough with sputum and fever. Laboratory testing showed a white blood cell count of 13.2 × 109/L (reference range: 3.97–9.15 × 109/L), a C-reactive protein level of 132.7 mg/L, a serum creatinine level of 280.3 µmol/L, and an elevated PR3-ANCA titer (366.4 RU/mL). Urinalysis demonstrated proteinuria (676.4 mg/24 hours) with microscopic hematuria. Thoracic CT revealed new lesions and pulmonary cavities in the bilateral lobes (Figure 7). The diagnosis was relapsing GPA with renal and pulmonary involvement and pulmonary infection. Progression of lung cancer could not be completely excluded, but the patient declined a biopsy. The patient was treated with antibiotics, antifungal agents, intravenous methylprednisolone, hemodialysis, and plasmapheresis, but his condition did not improve. A few days later, the patient experienced atrial tachycardia and lost consciousness; cardiopulmonary resuscitation was performed. The patient did not respond to treatment and subsequently died. The patient’s family refused autopsy; therefore, the possibility of lung cancer recurrence could not be excluded.
Figure 7. Chest computed tomography (CT) revealed new bilateral lung lesions in May 2017.
Discussion
There is increasing awareness of the association between malignant and autoimmune diseases in clinical practice.6 Cancer may increase the risk of some autoimmune diseases, and patients with autoimmune diseases may be at a higher risk for cancer.7,8 The mechanism underlying the bidirectional relationship between cancer and autoimmune diseases has yet to be elucidated.
AAV is an autoimmune disease that typically involves the upper and lower respiratory tract and kidney. Malignancy-associated vasculitis accounts for 0.4% to 4.2% of vasculitis cases.9–11 Previous studies have shown that solid tumors and lymphoid and myeloid cancers can develop in patients with circulating ANCA.2,9,12–14 Immunosuppressive treatment for AAV may accelerate the progression of malignant disease through immune suppression or by facilitating tumor immune evasion. Although rare, some reports have described the development of pulmonary malignant diseases in patients treated for AAV.15,16 In the present case, AAV manifested after pre-existing cancer. The initial presentation included pulmonary nodules, which were diagnosed as lung adenocarcinoma on the basis of histopathology. Malignant disease was controlled by cryoablation and chemotherapy; subsequently, the patient showed clinical signs and symptoms of AAV. Other reports have described lung cancer preceding or coinciding with autoimmune diseases such as IgA vasculitis, pauci-immune necrotizing crescentic glomerulonephritis, and sarcoidosis.17–20 The mechanisms by which cancer results in vasculitis are complex. Some speculate that tumors provoke inflammation, which may increase the risk of vasculitis in patients with cancer.9,10,12,13 In the present case, the chemotherapy administered to treat the cancer likely predisposed the patient to AAV. Several other reports describe chemotherapy-associated vasculitis in patients treated for a pre-existing cancer.21,22
Differentiating pulmonary manifestations of GPA from malignant lung lesions using thoracic CT is challenging. FDG-PET/CT imaging is an accurate tool for characterizing pulmonary nodules;23 however, inflammatory lung lesions can mimic malignant tumors by presenting with similar hypermetabolic activity on FDG-PET/CT,24 and this approach alone cannot be used to differentiate between inflammatory and malignant lesions in patients with GPA.25 We recommend that PET/CT be used in combination with a clinical examination and laboratory testing to reach the correct diagnosis. In the present case, PET/CT revealed increased FDG uptake in the bilateral upper lung lesions and enlarged mediastinal and right hilar lymph nodes, which supported the suspected diagnosis of malignancy. Despite this, a diagnosis of lung cancer did not completely explain the findings on pulmonary imaging and biopsy or the entirety of the patient’s clinical course. Therefore, we assumed that vasculitis was present before the pulmonary nodules developed, although there was no kidney involvement at that time. The patient initially underwent CT-guided percutaneous transthoracic lung biopsy for the mass in the left upper lobe. The diagnosis of lung cancer was confirmed, but the procedure provided a relatively small sample, and it is possible that the vasculitis could not have been seen in that specimen. Previous studies have suggested that transthoracic fine-needle aspiration may not be sufficiently accurate for diagnosing GPA with lung involvement.26,27 In one report, a lung nodule removed using video-assisted thoracoscopic surgery was pathologically diagnosed as concurrent GPA and lung squamous carcinoma.28 The characteristics of the right and left lung masses may have been inconsistent, and we did not repeat the biopsy for the mass in the right upper lobe to gain additional information regarding a diagnosis of vasculitis. Importantly, PET/CT did reveal soft tissue in the patient’s left sinuses, which did not exhibit increased FDG uptake (Figure 8). We interpreted these findings as suspected vasculitis in the nose. Finally, the bilateral lung lesions did not significantly decrease in size after chemotherapy and cryoablation, but the left lung mass decreased in size and the right lung mass and new nodules disappeared after treatment using corticosteroids and intravenous cyclophosphamide. Thus, it is possible that the bilateral lung lesions were related to vasculitis. Unfortunately, the patient died after experiencing relapsing GPA with renal complications and pulmonary infection.
Figure 8. Computed tomography (CT) revealed left sinusitis. (a) CT revealed mild mucosal thickening in the ethmoid, sphenoid, and left maxillary sinus. (b) Positron emission tomography showed no remarkable fluorodeoxyglucose uptake in the sinuses.
To our knowledge, this is the first published report of lung adenocarcinoma and granulomatous polyangiitis. These findings add to the clinical knowledge regarding the concurrent occurrence of malignant diseases and autoimmune diseases. Further research is required to understand the pathophysiological link between cancer and autoimmune diseases.
Supplemental Material
sj-pdf-1-imr-10.1177_0300060521993319 - Supplemental material for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report
Click here for additional data file.
Supplemental material, sj-pdf-1-imr-10.1177_0300060521993319 for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report by Chun-Yang Zhang, Ran Miao, Wei Li, Hao-Yong Ning, Xiang-En Meng, Zhi-Hai Han, Feng Qin, Ying-Kui Liang and Ming-Xv Li in Journal of International Medical Research
Declaration of conflicting interests: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Ying-Kui Liang https://orcid.org/0000-0003-1393-1587 | CISPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY-NC | 33596705 | 19,074,494 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sinusitis'. | Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report.
The relationship between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. A 66-year-old man presented with pulmonary nodules. Histological examination of a specimen from computed tomography-guided percutaneous transthoracic biopsy revealed adenocarcinoma. The patient was treated using cryoablation and systemic chemotherapy. Sixteen months later, the patient presented with fever, nasal inflammation, recurrent lung lesions, elevated serum creatinine levels, and high levels of ANCA. Histological examination of a specimen from ultrasound-guided percutaneous renal biopsy revealed pauci-immune necrotizing crescentic glomerulonephritis. The patient responded to treatment, but granulomatosis with polyangiitis recurred and he later died. This case highlights the possibility of sequential AAV with lung cancer. Although this is relatively rare, further research is needed to better understand the association or pathophysiological link between lung cancer and AAV.
Introduction
The association between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. Some studies have suggested an association or causative link between cancer and AAV,1–3 because AAV can occur in conjunction with other autoimmune diseases and is treated using immunosuppressive therapy,1,3–5 and cancer may be a potential risk factor for AAV.2
There are few reported cases of lung cancer diagnosed before, concurrently, or after AAV.1,2 Here, we present the case of a patient with lung adenocarcinoma who was treated using cryoablation and chemotherapy. The patient subsequently developed granulomatosis with polyangiitis (GPA) that presented as fever, nasal inflammation, and recurrent lung lesions, along with elevated levels of ANCAs and serum creatinine.
Case presentation
This study was approved by the Ethics Committee of The Sixth Medical Center of PLA General Hospital (approval no. HJQX2013-6-1). All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The patient consented to treatment before the initiation of any kind of treatment or procedure. Written informed consent to participate in this study and to publish images or data included in this article was obtained from the patient.
In 2011, a 66-year-old man presented with pulmonary nodules. After 2 years of active monitoring, the pulmonary nodules began to increase in size. The patient developed a mild cough with a small amount of bloody sputum. He had smoked 1.5 packs of cigarettes a day for the past 30 years and denied any family history of cancer or autoimmune diseases. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed metabolically active lesions with intense FDG uptake in the bilateral upper lung lobes (Figure 1). Computed tomography (CT)-guided percutaneous transthoracic biopsy was performed on the mass in the left upper lobe (Figure 2A). Pathological testing identified the mass as stage T2aN3M1a (grade IV) adenocarcinoma (Figure 2B) with no genomic mutations. Laboratory testing showed a C-reactive protein level of 5.1 mg/L (reference range: 0–8 mg/L) and a serum creatinine level of 94 µmol/L (reference range: 62–115 µmol/L); a urinalysis was normal. In April 2013, the patient underwent cryoablation of the bilateral upper lobe lesions (Figure 3A a and b). In May and September 2013, the patient underwent six cycles of paclitaxel and cisplatin chemotherapy.
Figure 1. Positron emission tomography (PET)/computed tomography (CT) revealed bilateral hypermetabolic lung lesions. (a) A CT revealed two nodules in the bilateral upper lung lobes. (b) PET imaging indicated abnormal fluorodeoxyglucose (FDG) uptake in the nodules. (c) A 3-dimensional maximum intensity projection reconstruction of the PET images demonstrated abnormal FDG uptake in the lung and lymph nodes.
Figure 2. Computed tomography (CT)-guided percutaneous transthoracic lung biopsy showing adenocarcinoma. (a) A CT-guided percutaneous transthoracic needle biopsy was performed on the mass in the left upper lobe. (b) Histopathology (hematoxylin and eosin staining) revealed adenocarcinoma.
Figure 3. Lung masses and lesions after computed tomography (CT)-guided cryoablation and chemotherapy. (a) CT after cryoablation of the mass in the left upper lung lobe (a, April 2013), the nodule in the right upper lung lobe (b, April 2013), and the nodule in the left upper lung lobe (c, May 2014). (b) The lung lesions were evaluated after cryoablation and chemotherapy, showing that the right upper lobe lesion had decreased in size, whereas the left upper lobe nodule had not (a and b, May 2014). Follow-up in October 2015 showed that both lesions, in the left and right upper lobes, had decreased in size (c and d).
In May 2014, the patient was referred to our center. Thoracic CT showed that the lesion in the left upper lobe had not markedly decreased in size (Figure 3B a and b). A third round of cryoablation was performed (Figure 3A c). Follow-up over a 6-month period with thoracic CT indicated that the tumor was clinically stable (Figure 3B c and d).
In September 2015, the patient presented with a stuffy nose, orbital and cheek pain, intermittent fever, and an axillary temperature of 37.2 to 39°C. Sinus CT demonstrated left sinusitis (Figure 4A and B). The patient was admitted to the otolaryngology department for sinus surgery. Histopathology confirmed sinusitis (Figure 4C) but the patient’s fever persisted.
Figure 4. Sinus computed tomography (CT) and hematoxylin and eosin-stained sections. Sinus coronal (a) and axial (b) CT images revealed soft tissue filling in the left maxillary sinus, with additional soft tissue in the bilateral ethmoid sinus and right maxillary sinus. (c) Histopathology after sinus surgery (hematoxylin and eosin staining) indicated sinusitis.
In November 2015, thoracic CT revealed new nodules in the right lung lobe (Figure 5A). Blood tests showed a serum creatinine level of 132.1 µmol/L, proteinuria (1765 mg/24 hours; reference range: 0–150 mg/24 hours) with hematuria, an elevated PR3-ANCA titer (423.6 relative units [RU]/mL; reference range: 0–20 RU/mL), and negative results on antiglomerular basement membrane testing. Histopathology of an ultrasound-guided percutaneous renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis (Figure 6). The diagnosis was AAV and GPA with renal, nose, and lung involvement. The patient received corticosteroids (intravenous methylprednisolone, 250 mg, once daily for 3 days, then oral methylprednisolone, 0.5 mg/kg, once daily and reduced by 8 mg every 4 weeks), plasmapheresis (six times in November and December 2015), intravenous cyclophosphamide (600 mg on Day 1 and 400 mg on Day 4, every 5 weeks, eight times, for a cumulative dose of 8000 mg), and methylprednisolone maintenance therapy (oral methylprednisolone, 10 mg, once daily). Following treatment, the patient’s fever subsided. In July 2016, thoracic CT revealed that the pulmonary lesions and new nodules had decreased in size or disappeared (Figure 5B). By January 2017, the patient’s PR3-ANCA titer had decreased to 106.5 RU/mL. The patient did not relapse while receiving cyclophosphamide, and oral methylprednisolone sustained remission.
Figure 5. New nodules in the right lung in November 2015. (A) Chest computed tomography (CT) revealed new nodules in the right lung (a–d). (B) The nodules disappeared (a–d) after treatment using corticosteroids, plasmapheresis, and intravenous cyclophosphamide, followed by maintenance therapy with methylprednisolone.
Figure 6. Histological examination (hematoxylin and eosin staining) of the ultrasound-guided percutaneous renal biopsy specimen revealed pauci-immune necrotizing crescentic glomerulonephritis.
In May 2017, the patient was readmitted for cough with sputum and fever. Laboratory testing showed a white blood cell count of 13.2 × 109/L (reference range: 3.97–9.15 × 109/L), a C-reactive protein level of 132.7 mg/L, a serum creatinine level of 280.3 µmol/L, and an elevated PR3-ANCA titer (366.4 RU/mL). Urinalysis demonstrated proteinuria (676.4 mg/24 hours) with microscopic hematuria. Thoracic CT revealed new lesions and pulmonary cavities in the bilateral lobes (Figure 7). The diagnosis was relapsing GPA with renal and pulmonary involvement and pulmonary infection. Progression of lung cancer could not be completely excluded, but the patient declined a biopsy. The patient was treated with antibiotics, antifungal agents, intravenous methylprednisolone, hemodialysis, and plasmapheresis, but his condition did not improve. A few days later, the patient experienced atrial tachycardia and lost consciousness; cardiopulmonary resuscitation was performed. The patient did not respond to treatment and subsequently died. The patient’s family refused autopsy; therefore, the possibility of lung cancer recurrence could not be excluded.
Figure 7. Chest computed tomography (CT) revealed new bilateral lung lesions in May 2017.
Discussion
There is increasing awareness of the association between malignant and autoimmune diseases in clinical practice.6 Cancer may increase the risk of some autoimmune diseases, and patients with autoimmune diseases may be at a higher risk for cancer.7,8 The mechanism underlying the bidirectional relationship between cancer and autoimmune diseases has yet to be elucidated.
AAV is an autoimmune disease that typically involves the upper and lower respiratory tract and kidney. Malignancy-associated vasculitis accounts for 0.4% to 4.2% of vasculitis cases.9–11 Previous studies have shown that solid tumors and lymphoid and myeloid cancers can develop in patients with circulating ANCA.2,9,12–14 Immunosuppressive treatment for AAV may accelerate the progression of malignant disease through immune suppression or by facilitating tumor immune evasion. Although rare, some reports have described the development of pulmonary malignant diseases in patients treated for AAV.15,16 In the present case, AAV manifested after pre-existing cancer. The initial presentation included pulmonary nodules, which were diagnosed as lung adenocarcinoma on the basis of histopathology. Malignant disease was controlled by cryoablation and chemotherapy; subsequently, the patient showed clinical signs and symptoms of AAV. Other reports have described lung cancer preceding or coinciding with autoimmune diseases such as IgA vasculitis, pauci-immune necrotizing crescentic glomerulonephritis, and sarcoidosis.17–20 The mechanisms by which cancer results in vasculitis are complex. Some speculate that tumors provoke inflammation, which may increase the risk of vasculitis in patients with cancer.9,10,12,13 In the present case, the chemotherapy administered to treat the cancer likely predisposed the patient to AAV. Several other reports describe chemotherapy-associated vasculitis in patients treated for a pre-existing cancer.21,22
Differentiating pulmonary manifestations of GPA from malignant lung lesions using thoracic CT is challenging. FDG-PET/CT imaging is an accurate tool for characterizing pulmonary nodules;23 however, inflammatory lung lesions can mimic malignant tumors by presenting with similar hypermetabolic activity on FDG-PET/CT,24 and this approach alone cannot be used to differentiate between inflammatory and malignant lesions in patients with GPA.25 We recommend that PET/CT be used in combination with a clinical examination and laboratory testing to reach the correct diagnosis. In the present case, PET/CT revealed increased FDG uptake in the bilateral upper lung lesions and enlarged mediastinal and right hilar lymph nodes, which supported the suspected diagnosis of malignancy. Despite this, a diagnosis of lung cancer did not completely explain the findings on pulmonary imaging and biopsy or the entirety of the patient’s clinical course. Therefore, we assumed that vasculitis was present before the pulmonary nodules developed, although there was no kidney involvement at that time. The patient initially underwent CT-guided percutaneous transthoracic lung biopsy for the mass in the left upper lobe. The diagnosis of lung cancer was confirmed, but the procedure provided a relatively small sample, and it is possible that the vasculitis could not have been seen in that specimen. Previous studies have suggested that transthoracic fine-needle aspiration may not be sufficiently accurate for diagnosing GPA with lung involvement.26,27 In one report, a lung nodule removed using video-assisted thoracoscopic surgery was pathologically diagnosed as concurrent GPA and lung squamous carcinoma.28 The characteristics of the right and left lung masses may have been inconsistent, and we did not repeat the biopsy for the mass in the right upper lobe to gain additional information regarding a diagnosis of vasculitis. Importantly, PET/CT did reveal soft tissue in the patient’s left sinuses, which did not exhibit increased FDG uptake (Figure 8). We interpreted these findings as suspected vasculitis in the nose. Finally, the bilateral lung lesions did not significantly decrease in size after chemotherapy and cryoablation, but the left lung mass decreased in size and the right lung mass and new nodules disappeared after treatment using corticosteroids and intravenous cyclophosphamide. Thus, it is possible that the bilateral lung lesions were related to vasculitis. Unfortunately, the patient died after experiencing relapsing GPA with renal complications and pulmonary infection.
Figure 8. Computed tomography (CT) revealed left sinusitis. (a) CT revealed mild mucosal thickening in the ethmoid, sphenoid, and left maxillary sinus. (b) Positron emission tomography showed no remarkable fluorodeoxyglucose uptake in the sinuses.
To our knowledge, this is the first published report of lung adenocarcinoma and granulomatous polyangiitis. These findings add to the clinical knowledge regarding the concurrent occurrence of malignant diseases and autoimmune diseases. Further research is required to understand the pathophysiological link between cancer and autoimmune diseases.
Supplemental Material
sj-pdf-1-imr-10.1177_0300060521993319 - Supplemental material for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report
Click here for additional data file.
Supplemental material, sj-pdf-1-imr-10.1177_0300060521993319 for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report by Chun-Yang Zhang, Ran Miao, Wei Li, Hao-Yong Ning, Xiang-En Meng, Zhi-Hai Han, Feng Qin, Ying-Kui Liang and Ming-Xv Li in Journal of International Medical Research
Declaration of conflicting interests: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Ying-Kui Liang https://orcid.org/0000-0003-1393-1587 | CISPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY-NC | 33596705 | 19,074,494 | 2021-02 |
What was the outcome of reaction 'Anti-neutrophil cytoplasmic antibody positive vasculitis'? | Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report.
The relationship between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. A 66-year-old man presented with pulmonary nodules. Histological examination of a specimen from computed tomography-guided percutaneous transthoracic biopsy revealed adenocarcinoma. The patient was treated using cryoablation and systemic chemotherapy. Sixteen months later, the patient presented with fever, nasal inflammation, recurrent lung lesions, elevated serum creatinine levels, and high levels of ANCA. Histological examination of a specimen from ultrasound-guided percutaneous renal biopsy revealed pauci-immune necrotizing crescentic glomerulonephritis. The patient responded to treatment, but granulomatosis with polyangiitis recurred and he later died. This case highlights the possibility of sequential AAV with lung cancer. Although this is relatively rare, further research is needed to better understand the association or pathophysiological link between lung cancer and AAV.
Introduction
The association between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. Some studies have suggested an association or causative link between cancer and AAV,1–3 because AAV can occur in conjunction with other autoimmune diseases and is treated using immunosuppressive therapy,1,3–5 and cancer may be a potential risk factor for AAV.2
There are few reported cases of lung cancer diagnosed before, concurrently, or after AAV.1,2 Here, we present the case of a patient with lung adenocarcinoma who was treated using cryoablation and chemotherapy. The patient subsequently developed granulomatosis with polyangiitis (GPA) that presented as fever, nasal inflammation, and recurrent lung lesions, along with elevated levels of ANCAs and serum creatinine.
Case presentation
This study was approved by the Ethics Committee of The Sixth Medical Center of PLA General Hospital (approval no. HJQX2013-6-1). All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The patient consented to treatment before the initiation of any kind of treatment or procedure. Written informed consent to participate in this study and to publish images or data included in this article was obtained from the patient.
In 2011, a 66-year-old man presented with pulmonary nodules. After 2 years of active monitoring, the pulmonary nodules began to increase in size. The patient developed a mild cough with a small amount of bloody sputum. He had smoked 1.5 packs of cigarettes a day for the past 30 years and denied any family history of cancer or autoimmune diseases. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed metabolically active lesions with intense FDG uptake in the bilateral upper lung lobes (Figure 1). Computed tomography (CT)-guided percutaneous transthoracic biopsy was performed on the mass in the left upper lobe (Figure 2A). Pathological testing identified the mass as stage T2aN3M1a (grade IV) adenocarcinoma (Figure 2B) with no genomic mutations. Laboratory testing showed a C-reactive protein level of 5.1 mg/L (reference range: 0–8 mg/L) and a serum creatinine level of 94 µmol/L (reference range: 62–115 µmol/L); a urinalysis was normal. In April 2013, the patient underwent cryoablation of the bilateral upper lobe lesions (Figure 3A a and b). In May and September 2013, the patient underwent six cycles of paclitaxel and cisplatin chemotherapy.
Figure 1. Positron emission tomography (PET)/computed tomography (CT) revealed bilateral hypermetabolic lung lesions. (a) A CT revealed two nodules in the bilateral upper lung lobes. (b) PET imaging indicated abnormal fluorodeoxyglucose (FDG) uptake in the nodules. (c) A 3-dimensional maximum intensity projection reconstruction of the PET images demonstrated abnormal FDG uptake in the lung and lymph nodes.
Figure 2. Computed tomography (CT)-guided percutaneous transthoracic lung biopsy showing adenocarcinoma. (a) A CT-guided percutaneous transthoracic needle biopsy was performed on the mass in the left upper lobe. (b) Histopathology (hematoxylin and eosin staining) revealed adenocarcinoma.
Figure 3. Lung masses and lesions after computed tomography (CT)-guided cryoablation and chemotherapy. (a) CT after cryoablation of the mass in the left upper lung lobe (a, April 2013), the nodule in the right upper lung lobe (b, April 2013), and the nodule in the left upper lung lobe (c, May 2014). (b) The lung lesions were evaluated after cryoablation and chemotherapy, showing that the right upper lobe lesion had decreased in size, whereas the left upper lobe nodule had not (a and b, May 2014). Follow-up in October 2015 showed that both lesions, in the left and right upper lobes, had decreased in size (c and d).
In May 2014, the patient was referred to our center. Thoracic CT showed that the lesion in the left upper lobe had not markedly decreased in size (Figure 3B a and b). A third round of cryoablation was performed (Figure 3A c). Follow-up over a 6-month period with thoracic CT indicated that the tumor was clinically stable (Figure 3B c and d).
In September 2015, the patient presented with a stuffy nose, orbital and cheek pain, intermittent fever, and an axillary temperature of 37.2 to 39°C. Sinus CT demonstrated left sinusitis (Figure 4A and B). The patient was admitted to the otolaryngology department for sinus surgery. Histopathology confirmed sinusitis (Figure 4C) but the patient’s fever persisted.
Figure 4. Sinus computed tomography (CT) and hematoxylin and eosin-stained sections. Sinus coronal (a) and axial (b) CT images revealed soft tissue filling in the left maxillary sinus, with additional soft tissue in the bilateral ethmoid sinus and right maxillary sinus. (c) Histopathology after sinus surgery (hematoxylin and eosin staining) indicated sinusitis.
In November 2015, thoracic CT revealed new nodules in the right lung lobe (Figure 5A). Blood tests showed a serum creatinine level of 132.1 µmol/L, proteinuria (1765 mg/24 hours; reference range: 0–150 mg/24 hours) with hematuria, an elevated PR3-ANCA titer (423.6 relative units [RU]/mL; reference range: 0–20 RU/mL), and negative results on antiglomerular basement membrane testing. Histopathology of an ultrasound-guided percutaneous renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis (Figure 6). The diagnosis was AAV and GPA with renal, nose, and lung involvement. The patient received corticosteroids (intravenous methylprednisolone, 250 mg, once daily for 3 days, then oral methylprednisolone, 0.5 mg/kg, once daily and reduced by 8 mg every 4 weeks), plasmapheresis (six times in November and December 2015), intravenous cyclophosphamide (600 mg on Day 1 and 400 mg on Day 4, every 5 weeks, eight times, for a cumulative dose of 8000 mg), and methylprednisolone maintenance therapy (oral methylprednisolone, 10 mg, once daily). Following treatment, the patient’s fever subsided. In July 2016, thoracic CT revealed that the pulmonary lesions and new nodules had decreased in size or disappeared (Figure 5B). By January 2017, the patient’s PR3-ANCA titer had decreased to 106.5 RU/mL. The patient did not relapse while receiving cyclophosphamide, and oral methylprednisolone sustained remission.
Figure 5. New nodules in the right lung in November 2015. (A) Chest computed tomography (CT) revealed new nodules in the right lung (a–d). (B) The nodules disappeared (a–d) after treatment using corticosteroids, plasmapheresis, and intravenous cyclophosphamide, followed by maintenance therapy with methylprednisolone.
Figure 6. Histological examination (hematoxylin and eosin staining) of the ultrasound-guided percutaneous renal biopsy specimen revealed pauci-immune necrotizing crescentic glomerulonephritis.
In May 2017, the patient was readmitted for cough with sputum and fever. Laboratory testing showed a white blood cell count of 13.2 × 109/L (reference range: 3.97–9.15 × 109/L), a C-reactive protein level of 132.7 mg/L, a serum creatinine level of 280.3 µmol/L, and an elevated PR3-ANCA titer (366.4 RU/mL). Urinalysis demonstrated proteinuria (676.4 mg/24 hours) with microscopic hematuria. Thoracic CT revealed new lesions and pulmonary cavities in the bilateral lobes (Figure 7). The diagnosis was relapsing GPA with renal and pulmonary involvement and pulmonary infection. Progression of lung cancer could not be completely excluded, but the patient declined a biopsy. The patient was treated with antibiotics, antifungal agents, intravenous methylprednisolone, hemodialysis, and plasmapheresis, but his condition did not improve. A few days later, the patient experienced atrial tachycardia and lost consciousness; cardiopulmonary resuscitation was performed. The patient did not respond to treatment and subsequently died. The patient’s family refused autopsy; therefore, the possibility of lung cancer recurrence could not be excluded.
Figure 7. Chest computed tomography (CT) revealed new bilateral lung lesions in May 2017.
Discussion
There is increasing awareness of the association between malignant and autoimmune diseases in clinical practice.6 Cancer may increase the risk of some autoimmune diseases, and patients with autoimmune diseases may be at a higher risk for cancer.7,8 The mechanism underlying the bidirectional relationship between cancer and autoimmune diseases has yet to be elucidated.
AAV is an autoimmune disease that typically involves the upper and lower respiratory tract and kidney. Malignancy-associated vasculitis accounts for 0.4% to 4.2% of vasculitis cases.9–11 Previous studies have shown that solid tumors and lymphoid and myeloid cancers can develop in patients with circulating ANCA.2,9,12–14 Immunosuppressive treatment for AAV may accelerate the progression of malignant disease through immune suppression or by facilitating tumor immune evasion. Although rare, some reports have described the development of pulmonary malignant diseases in patients treated for AAV.15,16 In the present case, AAV manifested after pre-existing cancer. The initial presentation included pulmonary nodules, which were diagnosed as lung adenocarcinoma on the basis of histopathology. Malignant disease was controlled by cryoablation and chemotherapy; subsequently, the patient showed clinical signs and symptoms of AAV. Other reports have described lung cancer preceding or coinciding with autoimmune diseases such as IgA vasculitis, pauci-immune necrotizing crescentic glomerulonephritis, and sarcoidosis.17–20 The mechanisms by which cancer results in vasculitis are complex. Some speculate that tumors provoke inflammation, which may increase the risk of vasculitis in patients with cancer.9,10,12,13 In the present case, the chemotherapy administered to treat the cancer likely predisposed the patient to AAV. Several other reports describe chemotherapy-associated vasculitis in patients treated for a pre-existing cancer.21,22
Differentiating pulmonary manifestations of GPA from malignant lung lesions using thoracic CT is challenging. FDG-PET/CT imaging is an accurate tool for characterizing pulmonary nodules;23 however, inflammatory lung lesions can mimic malignant tumors by presenting with similar hypermetabolic activity on FDG-PET/CT,24 and this approach alone cannot be used to differentiate between inflammatory and malignant lesions in patients with GPA.25 We recommend that PET/CT be used in combination with a clinical examination and laboratory testing to reach the correct diagnosis. In the present case, PET/CT revealed increased FDG uptake in the bilateral upper lung lesions and enlarged mediastinal and right hilar lymph nodes, which supported the suspected diagnosis of malignancy. Despite this, a diagnosis of lung cancer did not completely explain the findings on pulmonary imaging and biopsy or the entirety of the patient’s clinical course. Therefore, we assumed that vasculitis was present before the pulmonary nodules developed, although there was no kidney involvement at that time. The patient initially underwent CT-guided percutaneous transthoracic lung biopsy for the mass in the left upper lobe. The diagnosis of lung cancer was confirmed, but the procedure provided a relatively small sample, and it is possible that the vasculitis could not have been seen in that specimen. Previous studies have suggested that transthoracic fine-needle aspiration may not be sufficiently accurate for diagnosing GPA with lung involvement.26,27 In one report, a lung nodule removed using video-assisted thoracoscopic surgery was pathologically diagnosed as concurrent GPA and lung squamous carcinoma.28 The characteristics of the right and left lung masses may have been inconsistent, and we did not repeat the biopsy for the mass in the right upper lobe to gain additional information regarding a diagnosis of vasculitis. Importantly, PET/CT did reveal soft tissue in the patient’s left sinuses, which did not exhibit increased FDG uptake (Figure 8). We interpreted these findings as suspected vasculitis in the nose. Finally, the bilateral lung lesions did not significantly decrease in size after chemotherapy and cryoablation, but the left lung mass decreased in size and the right lung mass and new nodules disappeared after treatment using corticosteroids and intravenous cyclophosphamide. Thus, it is possible that the bilateral lung lesions were related to vasculitis. Unfortunately, the patient died after experiencing relapsing GPA with renal complications and pulmonary infection.
Figure 8. Computed tomography (CT) revealed left sinusitis. (a) CT revealed mild mucosal thickening in the ethmoid, sphenoid, and left maxillary sinus. (b) Positron emission tomography showed no remarkable fluorodeoxyglucose uptake in the sinuses.
To our knowledge, this is the first published report of lung adenocarcinoma and granulomatous polyangiitis. These findings add to the clinical knowledge regarding the concurrent occurrence of malignant diseases and autoimmune diseases. Further research is required to understand the pathophysiological link between cancer and autoimmune diseases.
Supplemental Material
sj-pdf-1-imr-10.1177_0300060521993319 - Supplemental material for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report
Click here for additional data file.
Supplemental material, sj-pdf-1-imr-10.1177_0300060521993319 for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report by Chun-Yang Zhang, Ran Miao, Wei Li, Hao-Yong Ning, Xiang-En Meng, Zhi-Hai Han, Feng Qin, Ying-Kui Liang and Ming-Xv Li in Journal of International Medical Research
Declaration of conflicting interests: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Ying-Kui Liang https://orcid.org/0000-0003-1393-1587 | Not recovered | ReactionOutcome | CC BY-NC | 33596705 | 19,074,494 | 2021-02 |
What was the outcome of reaction 'Glomerulonephritis rapidly progressive'? | Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report.
The relationship between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. A 66-year-old man presented with pulmonary nodules. Histological examination of a specimen from computed tomography-guided percutaneous transthoracic biopsy revealed adenocarcinoma. The patient was treated using cryoablation and systemic chemotherapy. Sixteen months later, the patient presented with fever, nasal inflammation, recurrent lung lesions, elevated serum creatinine levels, and high levels of ANCA. Histological examination of a specimen from ultrasound-guided percutaneous renal biopsy revealed pauci-immune necrotizing crescentic glomerulonephritis. The patient responded to treatment, but granulomatosis with polyangiitis recurred and he later died. This case highlights the possibility of sequential AAV with lung cancer. Although this is relatively rare, further research is needed to better understand the association or pathophysiological link between lung cancer and AAV.
Introduction
The association between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. Some studies have suggested an association or causative link between cancer and AAV,1–3 because AAV can occur in conjunction with other autoimmune diseases and is treated using immunosuppressive therapy,1,3–5 and cancer may be a potential risk factor for AAV.2
There are few reported cases of lung cancer diagnosed before, concurrently, or after AAV.1,2 Here, we present the case of a patient with lung adenocarcinoma who was treated using cryoablation and chemotherapy. The patient subsequently developed granulomatosis with polyangiitis (GPA) that presented as fever, nasal inflammation, and recurrent lung lesions, along with elevated levels of ANCAs and serum creatinine.
Case presentation
This study was approved by the Ethics Committee of The Sixth Medical Center of PLA General Hospital (approval no. HJQX2013-6-1). All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The patient consented to treatment before the initiation of any kind of treatment or procedure. Written informed consent to participate in this study and to publish images or data included in this article was obtained from the patient.
In 2011, a 66-year-old man presented with pulmonary nodules. After 2 years of active monitoring, the pulmonary nodules began to increase in size. The patient developed a mild cough with a small amount of bloody sputum. He had smoked 1.5 packs of cigarettes a day for the past 30 years and denied any family history of cancer or autoimmune diseases. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed metabolically active lesions with intense FDG uptake in the bilateral upper lung lobes (Figure 1). Computed tomography (CT)-guided percutaneous transthoracic biopsy was performed on the mass in the left upper lobe (Figure 2A). Pathological testing identified the mass as stage T2aN3M1a (grade IV) adenocarcinoma (Figure 2B) with no genomic mutations. Laboratory testing showed a C-reactive protein level of 5.1 mg/L (reference range: 0–8 mg/L) and a serum creatinine level of 94 µmol/L (reference range: 62–115 µmol/L); a urinalysis was normal. In April 2013, the patient underwent cryoablation of the bilateral upper lobe lesions (Figure 3A a and b). In May and September 2013, the patient underwent six cycles of paclitaxel and cisplatin chemotherapy.
Figure 1. Positron emission tomography (PET)/computed tomography (CT) revealed bilateral hypermetabolic lung lesions. (a) A CT revealed two nodules in the bilateral upper lung lobes. (b) PET imaging indicated abnormal fluorodeoxyglucose (FDG) uptake in the nodules. (c) A 3-dimensional maximum intensity projection reconstruction of the PET images demonstrated abnormal FDG uptake in the lung and lymph nodes.
Figure 2. Computed tomography (CT)-guided percutaneous transthoracic lung biopsy showing adenocarcinoma. (a) A CT-guided percutaneous transthoracic needle biopsy was performed on the mass in the left upper lobe. (b) Histopathology (hematoxylin and eosin staining) revealed adenocarcinoma.
Figure 3. Lung masses and lesions after computed tomography (CT)-guided cryoablation and chemotherapy. (a) CT after cryoablation of the mass in the left upper lung lobe (a, April 2013), the nodule in the right upper lung lobe (b, April 2013), and the nodule in the left upper lung lobe (c, May 2014). (b) The lung lesions were evaluated after cryoablation and chemotherapy, showing that the right upper lobe lesion had decreased in size, whereas the left upper lobe nodule had not (a and b, May 2014). Follow-up in October 2015 showed that both lesions, in the left and right upper lobes, had decreased in size (c and d).
In May 2014, the patient was referred to our center. Thoracic CT showed that the lesion in the left upper lobe had not markedly decreased in size (Figure 3B a and b). A third round of cryoablation was performed (Figure 3A c). Follow-up over a 6-month period with thoracic CT indicated that the tumor was clinically stable (Figure 3B c and d).
In September 2015, the patient presented with a stuffy nose, orbital and cheek pain, intermittent fever, and an axillary temperature of 37.2 to 39°C. Sinus CT demonstrated left sinusitis (Figure 4A and B). The patient was admitted to the otolaryngology department for sinus surgery. Histopathology confirmed sinusitis (Figure 4C) but the patient’s fever persisted.
Figure 4. Sinus computed tomography (CT) and hematoxylin and eosin-stained sections. Sinus coronal (a) and axial (b) CT images revealed soft tissue filling in the left maxillary sinus, with additional soft tissue in the bilateral ethmoid sinus and right maxillary sinus. (c) Histopathology after sinus surgery (hematoxylin and eosin staining) indicated sinusitis.
In November 2015, thoracic CT revealed new nodules in the right lung lobe (Figure 5A). Blood tests showed a serum creatinine level of 132.1 µmol/L, proteinuria (1765 mg/24 hours; reference range: 0–150 mg/24 hours) with hematuria, an elevated PR3-ANCA titer (423.6 relative units [RU]/mL; reference range: 0–20 RU/mL), and negative results on antiglomerular basement membrane testing. Histopathology of an ultrasound-guided percutaneous renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis (Figure 6). The diagnosis was AAV and GPA with renal, nose, and lung involvement. The patient received corticosteroids (intravenous methylprednisolone, 250 mg, once daily for 3 days, then oral methylprednisolone, 0.5 mg/kg, once daily and reduced by 8 mg every 4 weeks), plasmapheresis (six times in November and December 2015), intravenous cyclophosphamide (600 mg on Day 1 and 400 mg on Day 4, every 5 weeks, eight times, for a cumulative dose of 8000 mg), and methylprednisolone maintenance therapy (oral methylprednisolone, 10 mg, once daily). Following treatment, the patient’s fever subsided. In July 2016, thoracic CT revealed that the pulmonary lesions and new nodules had decreased in size or disappeared (Figure 5B). By January 2017, the patient’s PR3-ANCA titer had decreased to 106.5 RU/mL. The patient did not relapse while receiving cyclophosphamide, and oral methylprednisolone sustained remission.
Figure 5. New nodules in the right lung in November 2015. (A) Chest computed tomography (CT) revealed new nodules in the right lung (a–d). (B) The nodules disappeared (a–d) after treatment using corticosteroids, plasmapheresis, and intravenous cyclophosphamide, followed by maintenance therapy with methylprednisolone.
Figure 6. Histological examination (hematoxylin and eosin staining) of the ultrasound-guided percutaneous renal biopsy specimen revealed pauci-immune necrotizing crescentic glomerulonephritis.
In May 2017, the patient was readmitted for cough with sputum and fever. Laboratory testing showed a white blood cell count of 13.2 × 109/L (reference range: 3.97–9.15 × 109/L), a C-reactive protein level of 132.7 mg/L, a serum creatinine level of 280.3 µmol/L, and an elevated PR3-ANCA titer (366.4 RU/mL). Urinalysis demonstrated proteinuria (676.4 mg/24 hours) with microscopic hematuria. Thoracic CT revealed new lesions and pulmonary cavities in the bilateral lobes (Figure 7). The diagnosis was relapsing GPA with renal and pulmonary involvement and pulmonary infection. Progression of lung cancer could not be completely excluded, but the patient declined a biopsy. The patient was treated with antibiotics, antifungal agents, intravenous methylprednisolone, hemodialysis, and plasmapheresis, but his condition did not improve. A few days later, the patient experienced atrial tachycardia and lost consciousness; cardiopulmonary resuscitation was performed. The patient did not respond to treatment and subsequently died. The patient’s family refused autopsy; therefore, the possibility of lung cancer recurrence could not be excluded.
Figure 7. Chest computed tomography (CT) revealed new bilateral lung lesions in May 2017.
Discussion
There is increasing awareness of the association between malignant and autoimmune diseases in clinical practice.6 Cancer may increase the risk of some autoimmune diseases, and patients with autoimmune diseases may be at a higher risk for cancer.7,8 The mechanism underlying the bidirectional relationship between cancer and autoimmune diseases has yet to be elucidated.
AAV is an autoimmune disease that typically involves the upper and lower respiratory tract and kidney. Malignancy-associated vasculitis accounts for 0.4% to 4.2% of vasculitis cases.9–11 Previous studies have shown that solid tumors and lymphoid and myeloid cancers can develop in patients with circulating ANCA.2,9,12–14 Immunosuppressive treatment for AAV may accelerate the progression of malignant disease through immune suppression or by facilitating tumor immune evasion. Although rare, some reports have described the development of pulmonary malignant diseases in patients treated for AAV.15,16 In the present case, AAV manifested after pre-existing cancer. The initial presentation included pulmonary nodules, which were diagnosed as lung adenocarcinoma on the basis of histopathology. Malignant disease was controlled by cryoablation and chemotherapy; subsequently, the patient showed clinical signs and symptoms of AAV. Other reports have described lung cancer preceding or coinciding with autoimmune diseases such as IgA vasculitis, pauci-immune necrotizing crescentic glomerulonephritis, and sarcoidosis.17–20 The mechanisms by which cancer results in vasculitis are complex. Some speculate that tumors provoke inflammation, which may increase the risk of vasculitis in patients with cancer.9,10,12,13 In the present case, the chemotherapy administered to treat the cancer likely predisposed the patient to AAV. Several other reports describe chemotherapy-associated vasculitis in patients treated for a pre-existing cancer.21,22
Differentiating pulmonary manifestations of GPA from malignant lung lesions using thoracic CT is challenging. FDG-PET/CT imaging is an accurate tool for characterizing pulmonary nodules;23 however, inflammatory lung lesions can mimic malignant tumors by presenting with similar hypermetabolic activity on FDG-PET/CT,24 and this approach alone cannot be used to differentiate between inflammatory and malignant lesions in patients with GPA.25 We recommend that PET/CT be used in combination with a clinical examination and laboratory testing to reach the correct diagnosis. In the present case, PET/CT revealed increased FDG uptake in the bilateral upper lung lesions and enlarged mediastinal and right hilar lymph nodes, which supported the suspected diagnosis of malignancy. Despite this, a diagnosis of lung cancer did not completely explain the findings on pulmonary imaging and biopsy or the entirety of the patient’s clinical course. Therefore, we assumed that vasculitis was present before the pulmonary nodules developed, although there was no kidney involvement at that time. The patient initially underwent CT-guided percutaneous transthoracic lung biopsy for the mass in the left upper lobe. The diagnosis of lung cancer was confirmed, but the procedure provided a relatively small sample, and it is possible that the vasculitis could not have been seen in that specimen. Previous studies have suggested that transthoracic fine-needle aspiration may not be sufficiently accurate for diagnosing GPA with lung involvement.26,27 In one report, a lung nodule removed using video-assisted thoracoscopic surgery was pathologically diagnosed as concurrent GPA and lung squamous carcinoma.28 The characteristics of the right and left lung masses may have been inconsistent, and we did not repeat the biopsy for the mass in the right upper lobe to gain additional information regarding a diagnosis of vasculitis. Importantly, PET/CT did reveal soft tissue in the patient’s left sinuses, which did not exhibit increased FDG uptake (Figure 8). We interpreted these findings as suspected vasculitis in the nose. Finally, the bilateral lung lesions did not significantly decrease in size after chemotherapy and cryoablation, but the left lung mass decreased in size and the right lung mass and new nodules disappeared after treatment using corticosteroids and intravenous cyclophosphamide. Thus, it is possible that the bilateral lung lesions were related to vasculitis. Unfortunately, the patient died after experiencing relapsing GPA with renal complications and pulmonary infection.
Figure 8. Computed tomography (CT) revealed left sinusitis. (a) CT revealed mild mucosal thickening in the ethmoid, sphenoid, and left maxillary sinus. (b) Positron emission tomography showed no remarkable fluorodeoxyglucose uptake in the sinuses.
To our knowledge, this is the first published report of lung adenocarcinoma and granulomatous polyangiitis. These findings add to the clinical knowledge regarding the concurrent occurrence of malignant diseases and autoimmune diseases. Further research is required to understand the pathophysiological link between cancer and autoimmune diseases.
Supplemental Material
sj-pdf-1-imr-10.1177_0300060521993319 - Supplemental material for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report
Click here for additional data file.
Supplemental material, sj-pdf-1-imr-10.1177_0300060521993319 for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report by Chun-Yang Zhang, Ran Miao, Wei Li, Hao-Yong Ning, Xiang-En Meng, Zhi-Hai Han, Feng Qin, Ying-Kui Liang and Ming-Xv Li in Journal of International Medical Research
Declaration of conflicting interests: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Ying-Kui Liang https://orcid.org/0000-0003-1393-1587 | Not recovered | ReactionOutcome | CC BY-NC | 33596705 | 19,074,494 | 2021-02 |
What was the outcome of reaction 'Granulomatosis with polyangiitis'? | Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report.
The relationship between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. A 66-year-old man presented with pulmonary nodules. Histological examination of a specimen from computed tomography-guided percutaneous transthoracic biopsy revealed adenocarcinoma. The patient was treated using cryoablation and systemic chemotherapy. Sixteen months later, the patient presented with fever, nasal inflammation, recurrent lung lesions, elevated serum creatinine levels, and high levels of ANCA. Histological examination of a specimen from ultrasound-guided percutaneous renal biopsy revealed pauci-immune necrotizing crescentic glomerulonephritis. The patient responded to treatment, but granulomatosis with polyangiitis recurred and he later died. This case highlights the possibility of sequential AAV with lung cancer. Although this is relatively rare, further research is needed to better understand the association or pathophysiological link between lung cancer and AAV.
Introduction
The association between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. Some studies have suggested an association or causative link between cancer and AAV,1–3 because AAV can occur in conjunction with other autoimmune diseases and is treated using immunosuppressive therapy,1,3–5 and cancer may be a potential risk factor for AAV.2
There are few reported cases of lung cancer diagnosed before, concurrently, or after AAV.1,2 Here, we present the case of a patient with lung adenocarcinoma who was treated using cryoablation and chemotherapy. The patient subsequently developed granulomatosis with polyangiitis (GPA) that presented as fever, nasal inflammation, and recurrent lung lesions, along with elevated levels of ANCAs and serum creatinine.
Case presentation
This study was approved by the Ethics Committee of The Sixth Medical Center of PLA General Hospital (approval no. HJQX2013-6-1). All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The patient consented to treatment before the initiation of any kind of treatment or procedure. Written informed consent to participate in this study and to publish images or data included in this article was obtained from the patient.
In 2011, a 66-year-old man presented with pulmonary nodules. After 2 years of active monitoring, the pulmonary nodules began to increase in size. The patient developed a mild cough with a small amount of bloody sputum. He had smoked 1.5 packs of cigarettes a day for the past 30 years and denied any family history of cancer or autoimmune diseases. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed metabolically active lesions with intense FDG uptake in the bilateral upper lung lobes (Figure 1). Computed tomography (CT)-guided percutaneous transthoracic biopsy was performed on the mass in the left upper lobe (Figure 2A). Pathological testing identified the mass as stage T2aN3M1a (grade IV) adenocarcinoma (Figure 2B) with no genomic mutations. Laboratory testing showed a C-reactive protein level of 5.1 mg/L (reference range: 0–8 mg/L) and a serum creatinine level of 94 µmol/L (reference range: 62–115 µmol/L); a urinalysis was normal. In April 2013, the patient underwent cryoablation of the bilateral upper lobe lesions (Figure 3A a and b). In May and September 2013, the patient underwent six cycles of paclitaxel and cisplatin chemotherapy.
Figure 1. Positron emission tomography (PET)/computed tomography (CT) revealed bilateral hypermetabolic lung lesions. (a) A CT revealed two nodules in the bilateral upper lung lobes. (b) PET imaging indicated abnormal fluorodeoxyglucose (FDG) uptake in the nodules. (c) A 3-dimensional maximum intensity projection reconstruction of the PET images demonstrated abnormal FDG uptake in the lung and lymph nodes.
Figure 2. Computed tomography (CT)-guided percutaneous transthoracic lung biopsy showing adenocarcinoma. (a) A CT-guided percutaneous transthoracic needle biopsy was performed on the mass in the left upper lobe. (b) Histopathology (hematoxylin and eosin staining) revealed adenocarcinoma.
Figure 3. Lung masses and lesions after computed tomography (CT)-guided cryoablation and chemotherapy. (a) CT after cryoablation of the mass in the left upper lung lobe (a, April 2013), the nodule in the right upper lung lobe (b, April 2013), and the nodule in the left upper lung lobe (c, May 2014). (b) The lung lesions were evaluated after cryoablation and chemotherapy, showing that the right upper lobe lesion had decreased in size, whereas the left upper lobe nodule had not (a and b, May 2014). Follow-up in October 2015 showed that both lesions, in the left and right upper lobes, had decreased in size (c and d).
In May 2014, the patient was referred to our center. Thoracic CT showed that the lesion in the left upper lobe had not markedly decreased in size (Figure 3B a and b). A third round of cryoablation was performed (Figure 3A c). Follow-up over a 6-month period with thoracic CT indicated that the tumor was clinically stable (Figure 3B c and d).
In September 2015, the patient presented with a stuffy nose, orbital and cheek pain, intermittent fever, and an axillary temperature of 37.2 to 39°C. Sinus CT demonstrated left sinusitis (Figure 4A and B). The patient was admitted to the otolaryngology department for sinus surgery. Histopathology confirmed sinusitis (Figure 4C) but the patient’s fever persisted.
Figure 4. Sinus computed tomography (CT) and hematoxylin and eosin-stained sections. Sinus coronal (a) and axial (b) CT images revealed soft tissue filling in the left maxillary sinus, with additional soft tissue in the bilateral ethmoid sinus and right maxillary sinus. (c) Histopathology after sinus surgery (hematoxylin and eosin staining) indicated sinusitis.
In November 2015, thoracic CT revealed new nodules in the right lung lobe (Figure 5A). Blood tests showed a serum creatinine level of 132.1 µmol/L, proteinuria (1765 mg/24 hours; reference range: 0–150 mg/24 hours) with hematuria, an elevated PR3-ANCA titer (423.6 relative units [RU]/mL; reference range: 0–20 RU/mL), and negative results on antiglomerular basement membrane testing. Histopathology of an ultrasound-guided percutaneous renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis (Figure 6). The diagnosis was AAV and GPA with renal, nose, and lung involvement. The patient received corticosteroids (intravenous methylprednisolone, 250 mg, once daily for 3 days, then oral methylprednisolone, 0.5 mg/kg, once daily and reduced by 8 mg every 4 weeks), plasmapheresis (six times in November and December 2015), intravenous cyclophosphamide (600 mg on Day 1 and 400 mg on Day 4, every 5 weeks, eight times, for a cumulative dose of 8000 mg), and methylprednisolone maintenance therapy (oral methylprednisolone, 10 mg, once daily). Following treatment, the patient’s fever subsided. In July 2016, thoracic CT revealed that the pulmonary lesions and new nodules had decreased in size or disappeared (Figure 5B). By January 2017, the patient’s PR3-ANCA titer had decreased to 106.5 RU/mL. The patient did not relapse while receiving cyclophosphamide, and oral methylprednisolone sustained remission.
Figure 5. New nodules in the right lung in November 2015. (A) Chest computed tomography (CT) revealed new nodules in the right lung (a–d). (B) The nodules disappeared (a–d) after treatment using corticosteroids, plasmapheresis, and intravenous cyclophosphamide, followed by maintenance therapy with methylprednisolone.
Figure 6. Histological examination (hematoxylin and eosin staining) of the ultrasound-guided percutaneous renal biopsy specimen revealed pauci-immune necrotizing crescentic glomerulonephritis.
In May 2017, the patient was readmitted for cough with sputum and fever. Laboratory testing showed a white blood cell count of 13.2 × 109/L (reference range: 3.97–9.15 × 109/L), a C-reactive protein level of 132.7 mg/L, a serum creatinine level of 280.3 µmol/L, and an elevated PR3-ANCA titer (366.4 RU/mL). Urinalysis demonstrated proteinuria (676.4 mg/24 hours) with microscopic hematuria. Thoracic CT revealed new lesions and pulmonary cavities in the bilateral lobes (Figure 7). The diagnosis was relapsing GPA with renal and pulmonary involvement and pulmonary infection. Progression of lung cancer could not be completely excluded, but the patient declined a biopsy. The patient was treated with antibiotics, antifungal agents, intravenous methylprednisolone, hemodialysis, and plasmapheresis, but his condition did not improve. A few days later, the patient experienced atrial tachycardia and lost consciousness; cardiopulmonary resuscitation was performed. The patient did not respond to treatment and subsequently died. The patient’s family refused autopsy; therefore, the possibility of lung cancer recurrence could not be excluded.
Figure 7. Chest computed tomography (CT) revealed new bilateral lung lesions in May 2017.
Discussion
There is increasing awareness of the association between malignant and autoimmune diseases in clinical practice.6 Cancer may increase the risk of some autoimmune diseases, and patients with autoimmune diseases may be at a higher risk for cancer.7,8 The mechanism underlying the bidirectional relationship between cancer and autoimmune diseases has yet to be elucidated.
AAV is an autoimmune disease that typically involves the upper and lower respiratory tract and kidney. Malignancy-associated vasculitis accounts for 0.4% to 4.2% of vasculitis cases.9–11 Previous studies have shown that solid tumors and lymphoid and myeloid cancers can develop in patients with circulating ANCA.2,9,12–14 Immunosuppressive treatment for AAV may accelerate the progression of malignant disease through immune suppression or by facilitating tumor immune evasion. Although rare, some reports have described the development of pulmonary malignant diseases in patients treated for AAV.15,16 In the present case, AAV manifested after pre-existing cancer. The initial presentation included pulmonary nodules, which were diagnosed as lung adenocarcinoma on the basis of histopathology. Malignant disease was controlled by cryoablation and chemotherapy; subsequently, the patient showed clinical signs and symptoms of AAV. Other reports have described lung cancer preceding or coinciding with autoimmune diseases such as IgA vasculitis, pauci-immune necrotizing crescentic glomerulonephritis, and sarcoidosis.17–20 The mechanisms by which cancer results in vasculitis are complex. Some speculate that tumors provoke inflammation, which may increase the risk of vasculitis in patients with cancer.9,10,12,13 In the present case, the chemotherapy administered to treat the cancer likely predisposed the patient to AAV. Several other reports describe chemotherapy-associated vasculitis in patients treated for a pre-existing cancer.21,22
Differentiating pulmonary manifestations of GPA from malignant lung lesions using thoracic CT is challenging. FDG-PET/CT imaging is an accurate tool for characterizing pulmonary nodules;23 however, inflammatory lung lesions can mimic malignant tumors by presenting with similar hypermetabolic activity on FDG-PET/CT,24 and this approach alone cannot be used to differentiate between inflammatory and malignant lesions in patients with GPA.25 We recommend that PET/CT be used in combination with a clinical examination and laboratory testing to reach the correct diagnosis. In the present case, PET/CT revealed increased FDG uptake in the bilateral upper lung lesions and enlarged mediastinal and right hilar lymph nodes, which supported the suspected diagnosis of malignancy. Despite this, a diagnosis of lung cancer did not completely explain the findings on pulmonary imaging and biopsy or the entirety of the patient’s clinical course. Therefore, we assumed that vasculitis was present before the pulmonary nodules developed, although there was no kidney involvement at that time. The patient initially underwent CT-guided percutaneous transthoracic lung biopsy for the mass in the left upper lobe. The diagnosis of lung cancer was confirmed, but the procedure provided a relatively small sample, and it is possible that the vasculitis could not have been seen in that specimen. Previous studies have suggested that transthoracic fine-needle aspiration may not be sufficiently accurate for diagnosing GPA with lung involvement.26,27 In one report, a lung nodule removed using video-assisted thoracoscopic surgery was pathologically diagnosed as concurrent GPA and lung squamous carcinoma.28 The characteristics of the right and left lung masses may have been inconsistent, and we did not repeat the biopsy for the mass in the right upper lobe to gain additional information regarding a diagnosis of vasculitis. Importantly, PET/CT did reveal soft tissue in the patient’s left sinuses, which did not exhibit increased FDG uptake (Figure 8). We interpreted these findings as suspected vasculitis in the nose. Finally, the bilateral lung lesions did not significantly decrease in size after chemotherapy and cryoablation, but the left lung mass decreased in size and the right lung mass and new nodules disappeared after treatment using corticosteroids and intravenous cyclophosphamide. Thus, it is possible that the bilateral lung lesions were related to vasculitis. Unfortunately, the patient died after experiencing relapsing GPA with renal complications and pulmonary infection.
Figure 8. Computed tomography (CT) revealed left sinusitis. (a) CT revealed mild mucosal thickening in the ethmoid, sphenoid, and left maxillary sinus. (b) Positron emission tomography showed no remarkable fluorodeoxyglucose uptake in the sinuses.
To our knowledge, this is the first published report of lung adenocarcinoma and granulomatous polyangiitis. These findings add to the clinical knowledge regarding the concurrent occurrence of malignant diseases and autoimmune diseases. Further research is required to understand the pathophysiological link between cancer and autoimmune diseases.
Supplemental Material
sj-pdf-1-imr-10.1177_0300060521993319 - Supplemental material for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report
Click here for additional data file.
Supplemental material, sj-pdf-1-imr-10.1177_0300060521993319 for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report by Chun-Yang Zhang, Ran Miao, Wei Li, Hao-Yong Ning, Xiang-En Meng, Zhi-Hai Han, Feng Qin, Ying-Kui Liang and Ming-Xv Li in Journal of International Medical Research
Declaration of conflicting interests: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Ying-Kui Liang https://orcid.org/0000-0003-1393-1587 | Not recovered | ReactionOutcome | CC BY-NC | 33596705 | 19,074,494 | 2021-02 |
What was the outcome of reaction 'Pulmonary granuloma'? | Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report.
The relationship between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. A 66-year-old man presented with pulmonary nodules. Histological examination of a specimen from computed tomography-guided percutaneous transthoracic biopsy revealed adenocarcinoma. The patient was treated using cryoablation and systemic chemotherapy. Sixteen months later, the patient presented with fever, nasal inflammation, recurrent lung lesions, elevated serum creatinine levels, and high levels of ANCA. Histological examination of a specimen from ultrasound-guided percutaneous renal biopsy revealed pauci-immune necrotizing crescentic glomerulonephritis. The patient responded to treatment, but granulomatosis with polyangiitis recurred and he later died. This case highlights the possibility of sequential AAV with lung cancer. Although this is relatively rare, further research is needed to better understand the association or pathophysiological link between lung cancer and AAV.
Introduction
The association between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and lung cancer remains unclear. Some studies have suggested an association or causative link between cancer and AAV,1–3 because AAV can occur in conjunction with other autoimmune diseases and is treated using immunosuppressive therapy,1,3–5 and cancer may be a potential risk factor for AAV.2
There are few reported cases of lung cancer diagnosed before, concurrently, or after AAV.1,2 Here, we present the case of a patient with lung adenocarcinoma who was treated using cryoablation and chemotherapy. The patient subsequently developed granulomatosis with polyangiitis (GPA) that presented as fever, nasal inflammation, and recurrent lung lesions, along with elevated levels of ANCAs and serum creatinine.
Case presentation
This study was approved by the Ethics Committee of The Sixth Medical Center of PLA General Hospital (approval no. HJQX2013-6-1). All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The patient consented to treatment before the initiation of any kind of treatment or procedure. Written informed consent to participate in this study and to publish images or data included in this article was obtained from the patient.
In 2011, a 66-year-old man presented with pulmonary nodules. After 2 years of active monitoring, the pulmonary nodules began to increase in size. The patient developed a mild cough with a small amount of bloody sputum. He had smoked 1.5 packs of cigarettes a day for the past 30 years and denied any family history of cancer or autoimmune diseases. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed metabolically active lesions with intense FDG uptake in the bilateral upper lung lobes (Figure 1). Computed tomography (CT)-guided percutaneous transthoracic biopsy was performed on the mass in the left upper lobe (Figure 2A). Pathological testing identified the mass as stage T2aN3M1a (grade IV) adenocarcinoma (Figure 2B) with no genomic mutations. Laboratory testing showed a C-reactive protein level of 5.1 mg/L (reference range: 0–8 mg/L) and a serum creatinine level of 94 µmol/L (reference range: 62–115 µmol/L); a urinalysis was normal. In April 2013, the patient underwent cryoablation of the bilateral upper lobe lesions (Figure 3A a and b). In May and September 2013, the patient underwent six cycles of paclitaxel and cisplatin chemotherapy.
Figure 1. Positron emission tomography (PET)/computed tomography (CT) revealed bilateral hypermetabolic lung lesions. (a) A CT revealed two nodules in the bilateral upper lung lobes. (b) PET imaging indicated abnormal fluorodeoxyglucose (FDG) uptake in the nodules. (c) A 3-dimensional maximum intensity projection reconstruction of the PET images demonstrated abnormal FDG uptake in the lung and lymph nodes.
Figure 2. Computed tomography (CT)-guided percutaneous transthoracic lung biopsy showing adenocarcinoma. (a) A CT-guided percutaneous transthoracic needle biopsy was performed on the mass in the left upper lobe. (b) Histopathology (hematoxylin and eosin staining) revealed adenocarcinoma.
Figure 3. Lung masses and lesions after computed tomography (CT)-guided cryoablation and chemotherapy. (a) CT after cryoablation of the mass in the left upper lung lobe (a, April 2013), the nodule in the right upper lung lobe (b, April 2013), and the nodule in the left upper lung lobe (c, May 2014). (b) The lung lesions were evaluated after cryoablation and chemotherapy, showing that the right upper lobe lesion had decreased in size, whereas the left upper lobe nodule had not (a and b, May 2014). Follow-up in October 2015 showed that both lesions, in the left and right upper lobes, had decreased in size (c and d).
In May 2014, the patient was referred to our center. Thoracic CT showed that the lesion in the left upper lobe had not markedly decreased in size (Figure 3B a and b). A third round of cryoablation was performed (Figure 3A c). Follow-up over a 6-month period with thoracic CT indicated that the tumor was clinically stable (Figure 3B c and d).
In September 2015, the patient presented with a stuffy nose, orbital and cheek pain, intermittent fever, and an axillary temperature of 37.2 to 39°C. Sinus CT demonstrated left sinusitis (Figure 4A and B). The patient was admitted to the otolaryngology department for sinus surgery. Histopathology confirmed sinusitis (Figure 4C) but the patient’s fever persisted.
Figure 4. Sinus computed tomography (CT) and hematoxylin and eosin-stained sections. Sinus coronal (a) and axial (b) CT images revealed soft tissue filling in the left maxillary sinus, with additional soft tissue in the bilateral ethmoid sinus and right maxillary sinus. (c) Histopathology after sinus surgery (hematoxylin and eosin staining) indicated sinusitis.
In November 2015, thoracic CT revealed new nodules in the right lung lobe (Figure 5A). Blood tests showed a serum creatinine level of 132.1 µmol/L, proteinuria (1765 mg/24 hours; reference range: 0–150 mg/24 hours) with hematuria, an elevated PR3-ANCA titer (423.6 relative units [RU]/mL; reference range: 0–20 RU/mL), and negative results on antiglomerular basement membrane testing. Histopathology of an ultrasound-guided percutaneous renal biopsy demonstrated pauci-immune necrotizing crescentic glomerulonephritis (Figure 6). The diagnosis was AAV and GPA with renal, nose, and lung involvement. The patient received corticosteroids (intravenous methylprednisolone, 250 mg, once daily for 3 days, then oral methylprednisolone, 0.5 mg/kg, once daily and reduced by 8 mg every 4 weeks), plasmapheresis (six times in November and December 2015), intravenous cyclophosphamide (600 mg on Day 1 and 400 mg on Day 4, every 5 weeks, eight times, for a cumulative dose of 8000 mg), and methylprednisolone maintenance therapy (oral methylprednisolone, 10 mg, once daily). Following treatment, the patient’s fever subsided. In July 2016, thoracic CT revealed that the pulmonary lesions and new nodules had decreased in size or disappeared (Figure 5B). By January 2017, the patient’s PR3-ANCA titer had decreased to 106.5 RU/mL. The patient did not relapse while receiving cyclophosphamide, and oral methylprednisolone sustained remission.
Figure 5. New nodules in the right lung in November 2015. (A) Chest computed tomography (CT) revealed new nodules in the right lung (a–d). (B) The nodules disappeared (a–d) after treatment using corticosteroids, plasmapheresis, and intravenous cyclophosphamide, followed by maintenance therapy with methylprednisolone.
Figure 6. Histological examination (hematoxylin and eosin staining) of the ultrasound-guided percutaneous renal biopsy specimen revealed pauci-immune necrotizing crescentic glomerulonephritis.
In May 2017, the patient was readmitted for cough with sputum and fever. Laboratory testing showed a white blood cell count of 13.2 × 109/L (reference range: 3.97–9.15 × 109/L), a C-reactive protein level of 132.7 mg/L, a serum creatinine level of 280.3 µmol/L, and an elevated PR3-ANCA titer (366.4 RU/mL). Urinalysis demonstrated proteinuria (676.4 mg/24 hours) with microscopic hematuria. Thoracic CT revealed new lesions and pulmonary cavities in the bilateral lobes (Figure 7). The diagnosis was relapsing GPA with renal and pulmonary involvement and pulmonary infection. Progression of lung cancer could not be completely excluded, but the patient declined a biopsy. The patient was treated with antibiotics, antifungal agents, intravenous methylprednisolone, hemodialysis, and plasmapheresis, but his condition did not improve. A few days later, the patient experienced atrial tachycardia and lost consciousness; cardiopulmonary resuscitation was performed. The patient did not respond to treatment and subsequently died. The patient’s family refused autopsy; therefore, the possibility of lung cancer recurrence could not be excluded.
Figure 7. Chest computed tomography (CT) revealed new bilateral lung lesions in May 2017.
Discussion
There is increasing awareness of the association between malignant and autoimmune diseases in clinical practice.6 Cancer may increase the risk of some autoimmune diseases, and patients with autoimmune diseases may be at a higher risk for cancer.7,8 The mechanism underlying the bidirectional relationship between cancer and autoimmune diseases has yet to be elucidated.
AAV is an autoimmune disease that typically involves the upper and lower respiratory tract and kidney. Malignancy-associated vasculitis accounts for 0.4% to 4.2% of vasculitis cases.9–11 Previous studies have shown that solid tumors and lymphoid and myeloid cancers can develop in patients with circulating ANCA.2,9,12–14 Immunosuppressive treatment for AAV may accelerate the progression of malignant disease through immune suppression or by facilitating tumor immune evasion. Although rare, some reports have described the development of pulmonary malignant diseases in patients treated for AAV.15,16 In the present case, AAV manifested after pre-existing cancer. The initial presentation included pulmonary nodules, which were diagnosed as lung adenocarcinoma on the basis of histopathology. Malignant disease was controlled by cryoablation and chemotherapy; subsequently, the patient showed clinical signs and symptoms of AAV. Other reports have described lung cancer preceding or coinciding with autoimmune diseases such as IgA vasculitis, pauci-immune necrotizing crescentic glomerulonephritis, and sarcoidosis.17–20 The mechanisms by which cancer results in vasculitis are complex. Some speculate that tumors provoke inflammation, which may increase the risk of vasculitis in patients with cancer.9,10,12,13 In the present case, the chemotherapy administered to treat the cancer likely predisposed the patient to AAV. Several other reports describe chemotherapy-associated vasculitis in patients treated for a pre-existing cancer.21,22
Differentiating pulmonary manifestations of GPA from malignant lung lesions using thoracic CT is challenging. FDG-PET/CT imaging is an accurate tool for characterizing pulmonary nodules;23 however, inflammatory lung lesions can mimic malignant tumors by presenting with similar hypermetabolic activity on FDG-PET/CT,24 and this approach alone cannot be used to differentiate between inflammatory and malignant lesions in patients with GPA.25 We recommend that PET/CT be used in combination with a clinical examination and laboratory testing to reach the correct diagnosis. In the present case, PET/CT revealed increased FDG uptake in the bilateral upper lung lesions and enlarged mediastinal and right hilar lymph nodes, which supported the suspected diagnosis of malignancy. Despite this, a diagnosis of lung cancer did not completely explain the findings on pulmonary imaging and biopsy or the entirety of the patient’s clinical course. Therefore, we assumed that vasculitis was present before the pulmonary nodules developed, although there was no kidney involvement at that time. The patient initially underwent CT-guided percutaneous transthoracic lung biopsy for the mass in the left upper lobe. The diagnosis of lung cancer was confirmed, but the procedure provided a relatively small sample, and it is possible that the vasculitis could not have been seen in that specimen. Previous studies have suggested that transthoracic fine-needle aspiration may not be sufficiently accurate for diagnosing GPA with lung involvement.26,27 In one report, a lung nodule removed using video-assisted thoracoscopic surgery was pathologically diagnosed as concurrent GPA and lung squamous carcinoma.28 The characteristics of the right and left lung masses may have been inconsistent, and we did not repeat the biopsy for the mass in the right upper lobe to gain additional information regarding a diagnosis of vasculitis. Importantly, PET/CT did reveal soft tissue in the patient’s left sinuses, which did not exhibit increased FDG uptake (Figure 8). We interpreted these findings as suspected vasculitis in the nose. Finally, the bilateral lung lesions did not significantly decrease in size after chemotherapy and cryoablation, but the left lung mass decreased in size and the right lung mass and new nodules disappeared after treatment using corticosteroids and intravenous cyclophosphamide. Thus, it is possible that the bilateral lung lesions were related to vasculitis. Unfortunately, the patient died after experiencing relapsing GPA with renal complications and pulmonary infection.
Figure 8. Computed tomography (CT) revealed left sinusitis. (a) CT revealed mild mucosal thickening in the ethmoid, sphenoid, and left maxillary sinus. (b) Positron emission tomography showed no remarkable fluorodeoxyglucose uptake in the sinuses.
To our knowledge, this is the first published report of lung adenocarcinoma and granulomatous polyangiitis. These findings add to the clinical knowledge regarding the concurrent occurrence of malignant diseases and autoimmune diseases. Further research is required to understand the pathophysiological link between cancer and autoimmune diseases.
Supplemental Material
sj-pdf-1-imr-10.1177_0300060521993319 - Supplemental material for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report
Click here for additional data file.
Supplemental material, sj-pdf-1-imr-10.1177_0300060521993319 for Lung adenocarcinoma and sequential antineutrophil cytoplasmic antibody-associated vasculitis: a case report by Chun-Yang Zhang, Ran Miao, Wei Li, Hao-Yong Ning, Xiang-En Meng, Zhi-Hai Han, Feng Qin, Ying-Kui Liang and Ming-Xv Li in Journal of International Medical Research
Declaration of conflicting interests: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Ying-Kui Liang https://orcid.org/0000-0003-1393-1587 | Not recovered | ReactionOutcome | CC BY-NC | 33596705 | 19,074,494 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Deep vein thrombosis'. | Single-shot bevacizumab for cerebral radiation injury.
BACKGROUND
Cerebral radiation injury, including subacute radiation reactions and later stage radiation necrosis, is a severe side effect of brain tumor radiotherapy. A protocol of four infusions of the monoclonal antibody bevacizumab has been shown to be a highly effective treatment. However, bevacizumab is costly and can cause severe complications including thrombosis, bleeding and gastrointestinal perforations.
METHODS
We performed a retrospective analysis of patients treated in our clinic for cerebral radiation injury who received only a singular treatment with bevacizumab. Single-shot was defined as a singular administration of bevacizumab without a second administration during an interval of at least 6 weeks.
RESULTS
We identified 11 patients who had received a singular administration of bevacizumab to treat cerebral radiation injury. Prior radiation had been administered to treat gliomas (ten patients) or breast cancer brain metastases (one patient). 9 of 10 patients with available MRIs showed a marked reduction of edema at first follow-up. Discontinuation of Dexamethasone was possible in 6 patients and a significant dose reduction could be achieved in all other patients. One patient developed pulmonary artery embolism 2 months after bevacizumab administration. The median time to treatment failure of any cause was 3 months.
CONCLUSIONS
Single-shot bevacizumab therefore has meaningful activity in cerebral radiation injury, but durable control is rarely achieved. In patients where a complete protocol of four infusions with bevacizumab is not feasible due to medical contraindications or lack of reimbursement, single-shot bevacizumab treatment may be considered.
Background
Radiation necrosis has been reported in approximately 6 % of patients with brain tumors after radiation therapy and can lead to significant morbidity and, if untreated, mortality by progressive necrosis and brain edema [1]. Additionally, the risk of misinterpreting radiation injury (including subacute radiation reactions and later stage radiation necrosis) for tumor progression can prevent adequate therapy [2]. The risk of radiation injury is highest in patients who undergo repeated courses of radiotherapy, even with prolonged intervals between the two treatments. Lee et al. reported a rate of 64 % radiation necrosis for hypofractionated re-irradiation (45 Gy in 15 fractions) in glioma patients at least 12 months post-treatment [3]. Conceptually, radiation-induced injury is thought to result from damage to vascular endothelial and glial cells. Secretion of vascular endothelial growth factor (VEGF)-A appears to be responsible for edema formation via increasing vascular permeability and inducing a pro-inflammatory environment [4].
Bevacizumab is an antibody targeting VEGF-A induced angiogenesis and has been evaluated as a treatment for malignant brain tumors. While several phase III trials of first-line therapy failed to show any effect on overall survival [5–7], there was still a pronounced effect of bevacizumab on the blood brain barrier with reduced gadolinium contrast enhancement and edema reducing the rate of pseudoprogression in MRI scans from 9.3 to 2.2 % in the AVAglio trial [8]. Bevacizumab has also been used in small clinical trials as a treatment for radiation necrosis. Levin et al. reported a randomized, placebo-controlled trial of four infusions of bevacizumab 7.5 mg/kg at 3-week intervals for radiation necrosis of the central nervous system [9]. This trial demonstrated an impressive clinical and radiological improvement in all patients receiving bevacizumab while no patient with placebo treatment improved spontaneously. This treatment efficacy came at the cost of a high rate of adverse events in the bevacizumab group (6 of 11 patients) while no adverse events occurred in the placebo group. Common serious side effects of bevacizumab regimens include pulmonary artery embolism, venous thrombosis and intracranial hemorrhage [10, 11]. Whether a reduced number of bevacizumab cycles could also suffice to adequately treat radiation injury with a potentially reduced side effect profile remains unclear. In tumor treatment, clinical trials comparing standard and low-dose bevacizumab regimens found no significant differences in efficacy [12] but suggested a more favorable toxicity profile [13, 14].
Bevacizumab has not been approved by the European Medicines Agency (EMA), neither for progressive glioblastoma nor for the treatment of radiation reaction (FDA approval for adult patients with progressive glioblastoma) but is often used as an individual, off-label therapy for dexamethasone-refractory radiation necrosis or following steroid discontinuation due to adverse effects. In cases of rapid clinical deterioration, immediate treatment with bevacizumab can be considered to prevent permanent damage to eloquent areas. However, reimbursement by insurance companies can be difficult. If a singular administration (single-shot) of bevacizumab, that is considered financially affordable, was sufficient to treat cerebral radiation injury, this would broaden options for both, patients and physicians due to lower financial as well as potential side effect risks, especially for patients with prior vascular contraindications.
Methods
We performed a retrospective analysis of patients treated in our clinic between 2016 and 2019 to identify patients with cerebral radiation side effects who received a singular treatment with bevacizumab. Diagnosis of acute radiation reaction and radiation necrosis had been made in the interdisciplinary tumor board based on MRI and considering the field of radiation and the time from last radiation therapy (results section). Single-shot bevacizumab was defined as a singular administration of bevacizumab without a second administration during an interval of at least six weeks. The patient collective was evaluated with regard to histology, patient age at diagnosis of radiation injury, duration and maximum dose of dexamethasone, clinical course and possible side-effects, as well as the radiologic response to bevacizumab treatment. MRI scans included at least axial fluid-attenuated inversion recovery (FLAIR), T2-weighted, and T1-weighted images before and after application of gadolinium-based contrast agent. The extent of edema was estimated on the axial FLAIR or T2-weighted sequence. Response to bevacizumab treatment was defined as a reduction of the edema by at least 25 % [9].
Written consent by the individual patient for this retrospective data collection was waived by the ethics committee of the University Hospital Frankfurt; Goethe University which also approved the access to the patients’ data (IRB decision # 4/09, project SNO_01–08). Microsoft Excel was used for data management and analysis. Corel Draw 2019 was used to create figures.
Results
From 2016 until the end of 2019 approximately 400 patients received radiation of the brain for any reason (brain tumor or brain metastasis including primary therapy and re-irradiation therapy) at our cancer center. During this time, about 65 patients were treated with bevacizumab for radiation reaction. Retrospective analysis revealed 11 patients who were initially treated with a single-shot (Table 1). Ten patients had received prior fractionated radiation therapy for gliomas including 2 patients being treated primarily by radiotherapy at initial diagnosis (radiotherapy doses: 54 and 60 Gy) and 8 patients, who underwent re-irradiation for recurrent tumor (radiotherapy doses: 20–36 Gy), whereas one patient received re-irradiation (dose: 30 Gy) for recurrent brain metastasis of breast cancer after an initial radiosurgery.
Table 1 Patient characteristics
Number of Patients 11
Age at treatment with BEV [years]
Median (range) 47 (22 – 73)
Histology
Glioma 91% (10)
Brain metastasis (breast cancer) 9% (1)
Radiation for
Recurrent tumor 82% (9)
Primary therapy 18% (2)
Last radiation therapy prior to BEV [Gy]
5x4 18% (2)
10x3 9% (1)
10x3,5 36% (4)
12x3 9% (1)
15x2,67 9% (1)
30x1,8 9% (1)
30x2 9% (1)
Time from radiation to diagnosis of radiation injury [months]
Median (range) 2 (1-7)
Maximum Dose of dexamethasone [mg]
Before therapy, Median (range)
After therapy, Median (range)
8 (0 – 40)
0 (0 - 4)
Karnofsky-Score [%]
Before therapy, Median (range) 50 (40 – 80)
After therapy, Median (range) 60 (40 – 80)
Dose of BEV single-shot
7,5mg/kg 73% (8)
10mg/kg 27% (3)
Reported benefit by patient
Yes 64% (7)
No 36% (4)
Abbreviation: BEV bevacizumab
As soon as acute radiation reaction / radiation necrosis was diagnosed, therapy with dexamethasone was started or an already established therapy with steroids was intensified following a mean interval of 2 months post-radiation therapy. Median peak dose of dexamethasone was 8 mg/day, with a maximum dose of 40 mg/day in 2 patients. Diagnosis of radiation injury was based on MRI in 10 patients using additional MR-perfusion in 6 patients. In one patient, diagnosis was confirmed by positron emission tomography (F-18-fluroethyltyrosine). In no case had a biopsy been performed to confirm the diagnosis histologically.
When dexamethasone did not improve clinical symptoms or could not be tolerated at the required doses due to side effects, off-label treatment with bevacizumab was recommended at the institutional multidisciplinary tumor board. Four of these patients had a single-shot of bevacizumab treatment because of a high-risk situation for side effects rendering long-term repeat treatment with bevacizumab unfeasible (pulmonary embolism, deep vein thrombosis, fracture of several rips, hemorrhage of the tumor). In another patient there were concerns of possible increased toxicity as the patient received ongoing therapy with lomustin and temozolomide [15], and in a further patient bevacizumab was only administered once because of the ensuing palliative setting aimed at improving aphasia (Patient 1). Moreover, one patient initially received one singular infusion due to personal concerns with regard to side effects (patient 11), and two did not consent to further infusions (Patient 6 and patient 9). Two patients did not receive reimbursement by the insurance company for further treatment after the single-shot of bevacizumab.
Eight patients received 7.5 mg/kg as proposed by Levin et al., three patients received 10 mg/kg as used in the neuro-oncological trials for bevacizumab at that time [6, 9]. The treatment was well-tolerated without any acute side effects during the infusion. One patient with immobility developed deep vein thrombosis with subsequent pulmonary artery embolism two months after bevacizumab.
After a median interval of 55 days following the administration of bevacizumab first MRI showed a marked reduction of brain edema (at least 25 %) in 9/10 evaluable patients. An example is given in Fig. 1.
Fig. 1 MRI scans of a 34 year old patient with IDH-mutated astrocytoma. a MRI revealed a small recurrent tumor adjacent to the dorsal resection cavity with small surrounding edema. b The patient was treated with re-radiation therapy with 35 Gy and concomitant temozolomide. First MRI after the treatment showed an increase of contrast enhancement and edema which was diagnosed as radiation necrosis. c Therapy with 8 mg of dexamethasone did neither improve the MRI nor the clinical symptoms and bevacizumab 7.5 mg/kg was administered as a single-shot. d First scan one month later displayed a marked reduction in contrast enhancement and of the edema. Treatment with dexamethasone could be stopped. The follow up 3 months later was stable (not shown)
After single-shot bevacizumab, patients Karnofsky Performance Score (KPS) improved from a median of 50–60 % and 7 patients reported markedly improved clinical symptoms at the first visit after bevacizumab. Here, we noticed that the only slight improvement of KPS underestimated the clinical benefit in the activity of daily life. Indeed, the ability for an independent transfer from the wheelchair to a bed or toilet has a great impact on the patient’s quality of life that is not accurately reflected in the Karnofsky-Index. Notably, dexamethasone could be stopped in 6 of the patients. In all other patients, the dose of dexamethasone could be gradually reduced, finally reaching doses between 0.5 and 4 mg/day after a median time of 39 days after the single-shot.
Mean time to treatment failure was 3 months (range 1–10 months). Importantly, treatment failure to bevacizumab was due to tumor progression (patient 2, 4 and 6) or death (patient 1) in four patients, therefore, tumor progression should always be taken into account when interpreting clinical deterioration as the latter likely reflects a mixture of tumor progression and radiation necrosis (Fig. 2). One patient (patient 8) had both a marked improvement in clinical symptoms and MRI with a decline in contrast enhancement after single-shot. In this patient, however, treatment with bevacizumab was resumed 8 weeks after the first infusion, since the patient still experienced disabilities in the activities of daily life, and the single-shot had been tolerated well. Treatment failure in the other patients was diagnosed due to recurrent edema in follow-up MRI with or without clinical symptoms (Fig. 3).
Fig. 2 MRI scans of a 33 year old patient with IDH-wildtype glioblastoma. First (a) and second (b) MRI after resection and radiation therapy of recurrent glioblastoma showed not signs of tumor progression. Dexamethasone was started because of clinical deterioration before the third control (c) which showed a substantial increase in contrast enhancement and edema which were interpreted as late radiation necrosis. Bevacizumab 7.5 mg/kg was administered as a single-shot. d First scan 1.5 months later displayed a marked reduction of the edema while there was only a minor reduction of contrast enhancement. Diagnosis was changed from radiation necrosis to recurrent tumor
Fig. 3 Time to treatment failure. The swimmer plot shows the course of the individual patients labeled at the left side. The radiological diagnosis is indicated by color-coded dots (yellow: MRI, orange: MRI and MR-perfusion, purple: PET). The color-coded diamonds indicate the treatment failure of the single-shot bevacizumab (green: treatment of recurrent edema with corticosteroids, blue: treatment of recurrent edema with bevacizumab, blue border: resumed bevacizumab as the symptoms did not completely resolve, red: recurrent tumor, black: death of the patient because of recurrent tumor). Median time from single-shot to time of treatment failure of any cause) was three months
Discussion
Cerebral irradiation is an integral part of the treatment of brain cancer. One of the most severe complications is cerebral necrosis that can occur in patients with primary or metastatic brain tumors especially after a second course of irradiation for recurrent tumors. Despite promising efficacy in the treatment of cerebral radiation necrosis from smaller clinical trials, no application for bevacizumab approval for this indication has been filed. Reimbursement by insurance companies therefore remains difficult and is granted only on a case by case basis limiting the availability of bevacizumab. Assessing the efficacy of a singular bevacizumab treatment with a potentially more favorable side-effect profile and lesser financial burden than the cyclic treatment addresses a clinically important challenge. In the present work we show that a singular dose of bevacizumab resulted in significantly reduced edema on MRI sequences in all evaluable patients with two-thirds of patients reporting a meaningful improvement of clinical symptoms. In this context the very shot interval from radiation therapy to the development of brain lesions has to be noted. The mean time of two month is rather short for radiation necrosis in comparison to the trial by Levin et al. [9]. Therefore it is plausible that some of the patients suffered from a subacute or early delayed radiation reaction rather than manifest necrosis. Despite the small series, this study provides encouraging data, indicating that singular administration of bevacizumab might be a useful option for the treatment of radiation reaction / necrosis, especially in patients where prolonged bevacizumab treatment is not deemed feasible, as for example due to prior thromboembolic events or due to denial of therapy reimbursement. Additionally, even when bevacizumab is available for multiple treatments, a single-shot might be sufficient treatment for some patients. At the present time it is unclear whether a resumption of therapy in cases where a single-shot is not sufficient has disadvantages on the course of cerebral radiation necrosis.
In our analysis, we identified only one potentially severe side effect in one patient who was diagnosed with pulmonary artery embolism two months after bevacizumab. Whether this was instead attributable to immobility of the patient, who was later also diagnosed with deep vein thrombosis, or if this only contributed to the embolism remains unclear.
An interesting variant of the single-shot bevacizumab concept to further reduce the systemic side effects could be a local administration. The ongoing LIBERTI trial (NCT02819479) evaluates the efficacy of a single, intra-arterial dose of only 2.5 mg/kg bevacizumab [16]. Despite the large molecular mass of bevacizumab some penetration of the disrupted blood-brain barrier in regions of radiation injury appears possible [17]. The reduced side effect might come at the cost of a decreased duration of edema control. With a half-life of three weeks, the effect on the blood brain barrier might not be lasting, and the downside could be a rebound phenomenon with the need of bevacizumab re-challenge, as also indicated by the short time to treatment failure in our collective of only three months. The trial of Levin et al. with four administrations of 7.5 mg/ reported a relapse of radiation necrosis in 25 % of patients [9]. Zhuang et al. reported 14 patients with cerebral radiation necrosis who were treated with a lower dose of 5 mg/kg bevacizumab for at least 3 cycles of therapy [18]. MRI showed improvement in 13 of the 14 patients, but 10 of the 13 responsive patients exhibited a rebound phenomenon in the later follow-up. One option would be to further lower the dose of bevacizumab but keep the continuous administration. This approach of lowering the dose to 1 mg/kg bevacizumab every three weeks has revealed promising results in a phase 2 trial [19]. The trial included 21 patients and the grade of the edema index was improved in 19 patients. In contrast to Levin et al., no adverse events above grade 2 were reported. This concept has been further supported by case reports with low-dose bevacizumab and even longer intervals between the administration [20].
Prophylactic administration of a singular dose bevacizumab in high-risk situations (re-irradiation therapy, large irradiation fields or/and already present widespread edema prior to irradiation) could also be an option to consider. Thereby clinical deterioration might be prevented and the need for corticosteroids as well as the risk of a rebound effect after termination of bevacizumab treatment might be reduced. Such an approach has been explored in a phase 1 trial by Clarke et al. This trial included bevacizumab treatment to intensify the radiation dose of hypofractionated stereotactic re-irradiation [21]. This concept could be even more beneficial in cyber knife radiosurgery [22, 23].
While histological confirmation of cerebral radiation necrosis is clearly limited to only the most ambiguous cases, we here report a cohort of 11 patients whose radiological scans and dynamics indicated radiation necrosis. Two patients (patient 2 and 6) had treatment failure shortly after the single-shot due to tumor progress in the MRI and these were also patients where diagnosis was based on conventional MRI without MR-perfusion or MR-spectroscopy. A more selected collective of histologically diagnosed radiation necrosis could have shown more sustained effects of bevacizumab.
Conclusions
In summary, bevacizumab is an effective treatment for patients with cerebral radiation injury. Optimal dosing and intervals still have to be defined but most likely lower doses and longer intervals than investigated in previous trials [9] are sufficient. In the case of patients at high risk for side effects, single-shot of bevacizumab may be used as a test-dose and treatment can be continued when necessary.
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Acknowledgements
None.
Authors’ contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by M.V., K.W. E.F., MT.F. and M.W.R. The first draft of the manuscript was written by M.V., J.P.S. and M.W.R and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no specific funding for this work.
Availability of data and materials
Raw data were generated at the Dr. Senckenberg Institute of Neurooncology. The datasets generated are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written consent by the individual patient for this retrospective data collection was waived by the ethics committee of the University Hospital Frankfurt; Goethe University which also approved the access to the patients’ data (IRB decision # 4/09, project SNO_01–08).
Consent for publication
No individual person’s data is included in this article.
Competing interests
J.P.S. has received honoraria for lectures or advisory board participation, consulting or travel grants from Abbvie, Roche, Boehringer, Bristol-Myers Squibb, Medac, Mundipharma and UCB. M.W.R. has received a grant from UCB. The other authors report no conflict of interest. | BEVACIZUMAB | DrugsGivenReaction | CC BY | 33596839 | 18,986,888 | 2021-02-17 |
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